Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:11]2[CH:12]=[C:13]([C:16]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@H:21]([NH2:28])[CH2:20][C@@H:19]3[CH3:29])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(N(CC)CC)C.[C:47](OCC)(=[O:49])[CH3:48]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:11]2[CH:12]=[C:13]([C:16]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@H:21]([N:28]([C:47](=[O:49])[CH3:48])[C:34]4[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=4)[CH2:20][C@@H:19]3[CH3:29])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(C)=O
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)N1CCOc2ccc(C(=O)N3c4ccccc4[C@H](N)C[C@@H]3C)cc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCOc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-6-(4-Amino-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl)-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid ethyl ester (470 mg, 1.18 mmol) in methylene chloride was added 4-chlorophenylboronic acid (368 mg, 2.36 mmol), triethylamine (1.31 mL, 9.42 mmol) and copper(II)acetate (429 mg, 2.36 mmol). The heterogeneous green mixture was stirred open to air for 1 hour and then warmed to 60° C. and stirred over night (14 hours). The mixture was then cooled to room temperature, poured into rapidly stirred ethyl acetate (150 mL); solids were removed by filtration through Celite®. The extracts were washed several times with water and then once with brine. The extracts were then dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (95% methylene chloride/5% ethyl acetate) to afford the aniline product as a yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:30](=[O:32])N)[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:14]([C:23]([O:25]C(C)(C)C)=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)(=[O:37])C>C(O)C.O>[C:19]([O:18][C:16]([N:15]1[C@H:11]([CH2:10][CH:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:30]([OH:37])=[O:32])[CH2:12][CH2:13][C@H:14]1[C:23]([OH:25])=[O:24])=[O:17])([CH3:21])([CH3:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(NCc2ccccc2)C(N)=O)N1C(=O)OC(C)(C)C
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H](CC(NCc2ccccc2)C(=O)O)CC[C@H]1C(=O)O

Procedure:
2.2 g of di-tert-butyl (2S,5S)-5-(2-benzylamino-2-carbamoylethyl)pyrrolidine-1,2-dicarboxylate were dissolved in 20 ml of ethanol and 5 ml of water. 1.2 g of solid sodium hydroxide were added thereto. The solution was then boiled under reflux for 36 h. For workup, it was cooled to room temperature and neutralized with acetic acid, and the ethanol was removed in vacuo. The residue was diluted with 20 ml of water and adjusted to a pH of 3 with acetic acid. The mixture was extracted 3 times with 30 ml of 5:1 ethyl acetate/butanol each time. The organic phases were combined and concentrated in vacuo. The residue was chromatographed on silica gel.
Reaction SMILES: O[CH2:2][C:3]1[S:4][C:5]([CH3:10])=[C:6]([CH3:9])[C:7]=1[CH3:8].C(#N)C.[Br-:14].[C:15]1([PH+:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C>[Br-:14].[CH3:8][C:7]1[C:6]([CH3:9])=[C:5]([CH3:10])[S:4][C:3]=1[CH2:2][P+:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1sc(CO)c(C)c1C
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1sc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1C
Temperature: 50 °C

Procedure:
2.2 G. of 2-hydroxymethyl-3,4,5-trimethyl-thiophene were dissolved in 25 ml. of acetonitrile and 4.6 g. of triphenylphosphonium bromide were added. The resulting reaction mixture was heated to 50° C. for 3 hours. After evaporation of the solvent, the residue which formed was diluted with ethyl acetate, heated briefly and filtered. The crystalline (3,4,5-trimethyl-2-thenyl)-triphenyl phosphonium bromide obtained was dried at 50° C. under high vacuum and had m.p. 208°-215° C.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)[CH2:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C[C@H]1CC[C@H](CNC2C=CC(F)=C(F)C=2)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:31][C:26]1[CH:25]=[C:24]([N:15]([CH2:16][C@H:17]2[CH2:18][CH2:19][C@H:20]([CH3:23])[CH2:21][CH2:22]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C[C@H]2CC[C@H](C)CC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: C[C@H]1CC[C@H](CNc2ccc(F)c(F)c2)CC1
Product: C[C@H]1CC[C@H](CN(C(=O)Nc2ncc(SCC(=O)O)s2)c2ccc(F)c(F)c2)CC1

Procedure:
The title compound was prepared via {{2-[3-(3,4-difluoro-phenyl)-3-(trans-4-methylcyclohexylmethyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using trans-4-methyl-cyclohexylmethyl-(3,4-difluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl[C:14]([S:16]Cl)=[O:15].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][C:14](=[O:15])[S:16][N:8]=2)=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: O=C(Cl)SCl
Reactant: COc1cc(Cl)ccc1C(N)=O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(Cl)ccc1-c1nsc(=O)o1
Temperature: 90 °C
Yield: 95.6 %

Procedure:
To a solution of 4-chloro-2-methoxybenzamide (0.82 g, 4.42 mmol) in toluene (20 ml) was added chlorocarbonylsulfenyl chloride (0.73 ml, 8.84 mmol) under nitrogen atmosphere and the resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring) water was added followed by extraction with ether (3×50 ml). The combined organics was then sequentially washed with water, 10% NaHCO3 (aqueous solution) and finally again with water. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated to get desired product (1.03 g, 96% crude yield) that was carried forward as such without further purification. MS: 244.16 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:8](N(OC)C)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[O:9])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CON(C)C(=O)c1ncccc1F
Reactant: Br[Mg]c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1ncccc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-fluoro-N-methoxy-N-methylpyridine-2-carboxamide (4.8 g) in THF (100 mL) was added dropwise [4-(benzyloxy)phenyl]magnesium bromide (1 M solution in THF, 27.4 mL) at 0° C. After stirring at 0° C. for 2 h, the mixture was warmed to room temperature and stirred at room temperature overnight. The mixture was quenched with water and extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:21](=[O:24])(O)[O-].[Na+].[CH3:26][O:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=O)[CH2:33]Br)=[CH:30][CH:29]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=3)[CH2:33][C:32]([C:2]3[CH:7]=[CH:6][C:5]([O:24][CH3:21])=[CH:4][CH:3]=3)([C:31]3[CH:36]=[CH:37][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[N:20]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccc(Cl)cc2)cc1
Reactant: O=C([O-])O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2(c3ccc(OC)cc3)CN(c3ccc(S(C)(=O)=O)cc3)C(c3ccc(Cl)cc3)=N2)cc1
Temperature: 77.5 °C
Yield: 113.4 %

Procedure:
To a mixture of 4-chloro-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Example 1, Step 1) (700 mg, 2.24 mmol) and sodium bicarbonate (376 mg, 4.48 mmol) in isopropanol (50 mL), 4-methoxyphenacyl bromide (1.03 g, 4.48 mmol) was added. After heating the reaction mixture at 75-80° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with aqueous sodium bicarbonate and water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography (silica gel, hexane/ethyl acetate, 6/4) to give 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(4-methoxyphenyl)-1H-imidazole (695 mg, 71%) as a white solid: mp 110-113° C. Anal Calc'd. for C23H19N2SO3Cl: C, 62.94, H, 4.36, N, 6.38, S, 7.30. Found: C, 62.54, H, 4.43, N, 6.17, S, 7.15.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][C:20]3[NH:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)[C:19]=3[CH2:18]2)=[O:16])[CH2:9]1.[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[F:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][C:20]3[NH:23][N:24]=[C:25]([C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)[C:19]=3[CH2:18]2)=[O:16])[CH2:9]1
Reactant: O=C(NC1CCCNC1)N1CCc2[nH]nc(-c3ccncc3)c2C1
Reactant: O=Cc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1CCCN(Cc2ccccc2F)C1)N1CCc2[nH]nc(-c3ccncc3)c2C1
Reaction time: 16 h

Procedure:
In a flask, dichloromethane (0.295 mL) and acetic acid (2 drops) was added to N-(piperidin-3-yl)-3-(pyridin-4-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide trifluoroacetate salt (0.021 g, 0.05 mmol) and 2-fluorobenzaldehyde (0.0124 g, 0.1 mmol). The reaction was sonicated for 1 hr. Sodium triacetoxyborohydride (0.050 g, 0.25 mmol) was added in one portion. The reaction was stirred for an additional 16 hours. Saturated sodium bicarbarbonate (1 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (3×1 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by prep LC/MS. LC-MS: 435.68 [M+H]. LC/MS RT=1.82 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]([F:41])([F:40])[C:35]1([OH:39])[CH2:38][NH:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:37]3[CH2:38][C:35]([OH:39])([C:34]([F:41])([F:40])[F:33])[CH2:36]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: OC1(C(F)(F)F)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CC(O)(C(F)(F)F)C1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (70 mg, 0.151 mmol; Example 210, Step A) in DCE (3 mL) was added 53.8 mg (0.303 mmol) of 3-(trifluoromethyl)azetidin-3-ol hydrochloride (U.S. patent application publication no 2007/0275930) and sodium triacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring for 18 hours, the mixture was partitioned between water and DCM. The aqueous layer was washed with DCM. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated. The residue was purified by preparative thin layer chromatography on silica gel (eluent: 50% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN(C(C)C)C(C)C.[C:30]1([C:40](Cl)=[O:41])[C:39]2[C:34](=CC=CC=2)[CH:33]=[CH:32][CH:31]=1>ClCCl>[C:40]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)(=[O:41])[C:30]1[CH:39]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Step a): To a stirred solution of Intermediate 1 (ethyl (1,2,3,4-tetrahydro-pyrido[4,3b]indol-5-yl)-acetate hydrochloride, 25.0 mg, 0.085 mmol) and DIEA (73 μl, 0.425 mmol) in dichloromethane (0.5 ml) is added naphthoyl chloride (15 mg, 0.11 mmol). The resulting yellow solution was kept stirring at rt for 1 h and then is quenched by adding saturated aqueous NaHCO3 solution (2 ml). The organic layer is separated and washed with water (2 ml). After removal of the solvent, crude ethyl (2-benzoyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate is obtained pure as a yellow glassy solid: tR (LC-2) 2.20 min; ESI-MS (positive ion): m/z 386.31 [M+Na]+ (calcd 362.42 for C22H22N2O3).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.[O:16]1[CH2:19][C:18](=O)[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:16]1[CH2:19][CH:18]([N:1]2[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:2]2)[CH2:17]1
Reactant: O=C1COC1
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CN(C2COC2)CCO1
Reaction time: 0.08 h

Procedure:
To a solution of tert-butyl morpholin-2-ylmethylcarbamate (0.50 g) in dichloromethane (5 mL) was added oxetan-3-one (0.20 g). After stirring for 5 minutes, sodium triacetoxyborohydride (0.735 g) was added. After stirring for 2 hours, the reaction was diluted with dichloromethane (50 mL) and quenched with saturated NaHCO3 solution (50 mL). The organic layer was separated, washed with brine (40 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Reveleris 80 g) eluting with a gradient of 0.5% to 5% methanol/dichloromethane over 40 minutes (flow=40 ml/minute) gave the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:20]#[N:21])=[N:4][C:5]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]3[CH2:19][CH2:18]3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:7]=1.[OH:22][CH:23]1[CH2:27][CH2:26][O:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH:17]1([N:13]2[CH2:14][CH2:15][CH2:16][N:10]([C:8]([C:5]3[N:4]=[C:3]([C:20]#[N:21])[C:2]([O:22][CH:23]4[CH2:27][CH2:26][O:25][CH2:24]4)=[CH:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:19][CH2:18]1
Reactant: OC1CCOC1
Reactant: N#Cc1nc(C(=O)N2CCCN(C3CC3)CC2)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1nc(C(=O)N2CCCN(C3CC3)CC2)ccc1OC1CCOC1
Temperature: 150 °C
Yield: 45.9 %

Procedure:
A mixture of 3-bromo-6-(4-cyclopropyl-[1,4]diazepane-1-carbonyl)-pyridine-2-carbonitrile (0.600 g, 1.71 mmol), 3-hydroxytetrahydrofuran (301 mg, 3.41 mmol), and anhydrous Cs2CO3 (1.67 g, 5.13 mmol) in DMSO (7 mL) was heated by microwave irradiation at 150° C. for 35 min. The mixture was diluted with water and extracted with Et2O. The combined organic layers were dried (Na2CO3) and concentrated. The residue was purified by FCC to give the title compound (280 mg, 46%). MS (ESI): mass calcd. for C19H24N4O3, 356.4; m/z found, 357.5 [M+H]+. 1H NMR (CDCl3): 7.94 (d, J=8.8 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 5.08-5.04 (m, 1H), 4.12-3.93 (m, 4H), 3.77-3.72 (m, 2H), 3.69-3.63 (m, 2H), 2.98-2.92 (m, 2H), 2.87-2.81 (m, 2H), 2.35-2.25 (m, 1H), 2.25-2.18 (m, 1H), 1.97-1.83 (m, 3H), 0.51-0.35 (m, 4H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[C:12]([N+:21]([O-])=O)[CH:11]=1.O1CCCC1>O.C(O)C>[NH2:21][C:12]1[CH:11]=[C:10]([CH3:9])[CH:15]=[CH:14][C:13]=1[N:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1
Reactant: Cc1ccc(-n2cccc2)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-n2cccc2)c(N)c1

Procedure:
20 g of sodium hydrosulfite are added portionwise to a solution of 18.18 g (0.09 mole) of 1-(4-methyl-2-nitrophenyl)pyrrole in 400 ml. of tetrahydrofuran and 200 ml. of water. The resulting solution is heated on a steam bath for 5 minutes and an additional 20 g. of sodium hydrosulfite are added and the solution is heated for 5 minutes on a steam bath. Then 38.3 g. of sodium hydrosulfite and a solution of 400 ml. of ethanol and 500 ml. of water are added, and again the solution is heated on a steam bath for 5 minutes. The solvent is removed to give a tan solid which is recrystallized from hexane to give white crystals, m.p. 89°-90° C. of 1-(2-amino-4-methylphenyl)pyrrole.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=O.[CH2:11](N(CC)CC)C.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C)C1C=CN=CC=1>[C:18]([N:1]1[CH:2]([C:8](=[O:10])[CH3:11])[CH2:3][CH2:4][C:5]1=[O:7])(=[O:20])[CH3:19]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Product: CC(=O)C1CCC(=O)N1C(C)=O

Procedure:
Following the method of W. Steglich, et al., Liebigs, Ann. Chem., 1753, 1974, (21.0 gm) of glutamic acid in 75 ml of acetic anhydride, 150 mg of 4-dimethylamino-pyridine, and 75 ml of triethylamine was heated 60° C. overnight. The reaction mixture was then concentrated in vacuo, the residue taken up in dichloromethane and washed with water. The organic portion was treated with charcoal, filtered, concentrated and 1,5-diacetyl-2-pyrroidone was obtained crystalline from ether-dichloromethane, mp 62° C. 'H NMR (δ CDCl3): 1.8-2.8 (m, CH2), 2.3 (s, 3H, CH3), 2.55 (s, 3H, CH3), 4.8-5.0 ppm (dd, 1H, CHN).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](O[C:33](=[O:35])[CH3:34])OC(=O)C)(=O)C.[Na+].[C:37]([OH:40])(=O)[CH3:38].O>C(Cl)Cl>[CH2:1]([C:8]1[C:9]([CH:18]([NH:22][CH2:1][CH2:8][CH2:9][N:10]2[C:33](=[O:35])[C:34]3[C:38](=[CH:7][CH:2]=[CH:3][CH:4]=3)[C:37]2=[O:40])[CH:19]([CH3:20])[CH3:21])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)O
Reactant: CC(C)C(N)c1nc2ccccc2cc1Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2ccccc2cc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-benzylquinolin-2-yl)-2-methylpropan-1-amine 15 (31 mg, 1 eq.) in CH2Cl2 (3 ml), was added aldehyde 16 (0.8 eq., 17 mg), sodium triacetoxy borohydride, and acetic acid. The reaction mixture was stirred for 3 h at room temperature. Water was added and then the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to yield 46 mg of 2-(3-{[1-(3-benzylquinolin-2-yl)-2-methylpropyl]amino}propyl)-1H-isoindole-1,3(2H)-dione 17.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[Br:19]N1C(=O)CCC1=O.C(N(CC)CC)C.O>C(#N)C>[Br:19][CH:9]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(/C=C/B2OC(C)(C)C(C)(C)O2)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(C=CBr)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of (E)-2-methyl-5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)-pyridine (1.0 g, 4.08 mmol; Example 23B) in acetonitrile (10 mL) was treated with N-bromosuccinimide (0.346 mL, 4.08 mmol; Aldrich) and triethylamine (0.625 mL, 4.49 mmol; Aldrich) and stirred at room temperature for 16 hours. Water was added and the mixture was extracted several times with ethyl acetate. The combined organic extracts were concentrated, and the resulting material was purified by flash chromatography (silica gel, hexane/ethyl acetate, 3:1) to afford the title compound as a 1.2:1 Z/E mixture: 1H NMR (300 MHz, CDCl3) δ ppm 2.54 (s, 3H), 2.57 (s, 3.6H), 6.52 (d, J=14 Hz, 1.2H), 6.75-6.85 (d, J=14 Hz, 1H), 7.01-7.22 (m, 4.4H), 7.52 (dd, J=8, 2 Hz, 1H), 8.07 (dd, J=8, 2 Hz, 1.2H), 8.43 (d, J=2 Hz, 1H), 8.66 (d, J=2 Hz, 1.2H); MS (DCI/NH3) m/z 198/200 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2.[Li+].CC([N-]C(C)C)C.Br[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[CH2:23][CH2:28][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH2:8][CH2:9][C:10]1=[O:13]
Reactant: COC(=O)C(C)Br
Reactant: COc1cccc2c1CC(=O)CC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CCC1C(=O)CCc2cccc(OC)c21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 62.1 %

Procedure:
A three-neck, round-bottomed flask, equipped with a dropping funnel and septum, was charged with 1.76 g (10 mmol) of 8-methoxy-2-tetralone and 20 mL of THF under a nitrogen atmosphere. The solution was cooled to -30° C. and 7.5 mL (11 mmol) of LDA (1.5M in cyclohexane) was added dropwise. The solution was stirred for 30 minutes and warmed to 0° C. To this solution, 1.3 mL (12 mmol) of methyl bromopropionate was added. The solution was stirred at room temperature for two hours. The reaction was quenched with 3 N HCl until pH of the mixture was <3. THF was removed in vacuo and the concentrate was extracted with methylene chloride (2×500 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. This oil was purified by liquid chromatography on 400 g silica gel 60 (230-400 m), eluting with hexane-acetone (4:1), and collecting 40 mL fractions. Fractions homogeneous by TLC were combined and concentrated in vacuo to give 1.63 g (63%) of the title compound as a yellow oil.