Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](=[O:5])[CH3:4].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br-].[CH2:19]([C:21]([C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)([C:24]1[S:25][CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:22][CH3:23])[CH3:20].C1COCC1>C1COCC1.CCOC(C)=O>[CH2:19]([C:21]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:4][C:3](=[O:5])[C:2]([CH3:7])([CH3:6])[CH3:1])=[C:32]([CH3:37])[CH:31]=1)([C:24]1[S:25][CH:26]=[C:27]([CH3:29])[CH:28]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCC(CC)(c1ccc(C)c(C)c1)c1cc(C)cs1
Reactant: CC(=O)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(CCC(=O)C(C)(C)C)c(C)c1)c1cc(C)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a 0° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanol (6 g,) in THF (50 ml) is treated with PBr3 (2.2 ml, 23.3 mmol) and warmed to RT. After stirring for 2 h, the mixture is partitioned between EtOAc and brine. The organic layer is MgSO4 dried, concentrated, and dissolved in anhydrous THF (30 ml) to give a solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methane bromide. Separately, a solution of 3,3-dimethyl-butan-2-one (5.3 ml, 42.4 mmol) in THF (15 ml) is treated with LiHMDS (42.4 ml, 42.4 mmol, 1M in THF) at −70° C. for 1 h. This solution is transferred (via cannula) into a −70° C. solution of {4-[1-ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenyl}-methanebromide/THF. The mixture is warmed to RT and stirred for 1 h. The reaction is diluted with EtOAc and washed with 0.2 N HCl until the aq layer is pH 2. The organic layer is concentrated to give the title compound (6.2 g, 79%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:29])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc2c(c1)S(=O)c1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40.7 %

Procedure:
Dissolve 2 gm (0.0071 moles) of the ester of Example 2 in 200 cc of chloroform and 1.396 gm of m-chloroperbenzoic acid and stir at room temperature for 20 minutes. Add successive 100 mg portions of m-chloroperbenzoic acid until thin layer chromatography slows conversion of the starting material. Basify with calcium hydroxide and separate the solids. Chromotograph the solids over silica gel eluting with 30% ethyl acetate in benzene to obtain the title product (yield 870 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[Br:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cncc(Br)n1
Reactant: OB(O)c1ccccc1
Product: Brc1cncc(-c2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 2,6-dibromo-pyrazine and phenylboronic acid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=[O:20])[CH:14]=[C:9]12)(=[O:3])[CH3:2].[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>CN(C=O)C>[CH3:21][N:22]([CH3:24])[CH:23]=[CH:2][C:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][N:8]1[C:18](=[O:19])[CH2:17][NH:16][C:15](=[O:20])[CH:14]=[C:9]12)=[O:3]
Reactant: CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccc2c1CCN1C(=O)CNC(=O)C=C21
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.1 %

Procedure:
100-2. A mixture of 9-acetyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (200 mg, 0.74 mmol) in DMF (1.0 mL) was treated with DMF-DMA (0.12 mL, 0.89 mmol) and stirred at 100° C. for 1 h. The mixture was concentrated in vacuo and the crude product obtained was purified by flash chromatography (SiO2, DCM/MeOH 98:2 to 85:15) to give the title compound (135 mg) as a beige solid. UPLC-MS: MS 236.2 (M+H+), UPLC rt 0.54 min.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[CH2:4]1.CCCCCC.C(O)(C)C.C(NCC)C>>[CH3:1][N:2]([CH3:14])[C@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[CH2:4]1.[CH3:1][N:2]([CH3:14])[C@@H:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CN(C)C1CCc2ccc(N)cc2C1
Solvent: CC(C)O
Solvent: CCNCC
Solvent: CCCCCC
Product: CN(C)[C@@H]1CCc2ccc(N)cc2C1
Product: CN(C)[C@H]1CCc2ccc(N)cc2C1

Procedure:
N2,N2-dimethyl-1,2,3,4-tetrahydronaphthalene-2,7-diamine was optically resolved with CHIRALPAK AD-H (20 mm×250 mm) (hexane/isopropanol/diethylamine=80/20/0.1) to obtain 144 mg of (2S*)—N2,N2-dimethyl-1,2,3,4-tetrahydronaphthalene-2,7-diamine as a white solid, and 146 mg of (2R*)—N2,N2-dimethyl-1,2,3,4-tetrahydronaphthalene-2,7-diamine as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:20]([O:22][CH3:23])=[O:21])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[N:8]=1)[CH2:2][CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:37]2[C:41]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[CH:53]=[CH:52][C:51]([CH2:54]Br)=[CH:50][CH:49]=3)=[N:40][N:39]=[N:38]2)C=CC=CC=1>CN(C=O)C>[O:19]=[C:14]([C:10]1[N:9]([C:7]2[N:8]=[C:4]([CH2:1][CH2:2][CH3:3])[N:5]([CH2:54][C:51]3[CH:52]=[CH:53][C:48]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[C:41]4[NH:37][N:38]=[N:39][N:40]=4)=[CH:49][CH:50]=3)[C:6]=2[C:20]([O:22][CH3:23])=[O:21])[CH:13]=[CH:12][CH:11]=1)[C:15]([F:17])([F:16])[F:18]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)OC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
Methyl 2-propyl-4-[2-(1-oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]imidazole-5-carboxylate (15 g, 0.046 mol) from Example 6 was dissolved in DMF (500 mL) and Cs2CO3 (32.9 g, 0.1 mol) added. After 5 minutes, N-triphenylmethyl-5-[4, (bromomethyl)-biphenyl-2-yl]tetrazole (Example 12, 26.9 g, 0.048 mol) was added and the reaction mixture stirred at room temperature for 6 hours. The reaction was filtered to remove insoluble salts and the DMF removed high vacuum. The residue was partitioned between ethyl acetate (150 mL) and water (50 mL). The organic layer was extracted with brine, dried over anhydrous magnesium sulfate, and the solvent evaporated under reduced pressure. Chromatography of the residue on silica gel, eluting with a gradient of ethyl acetate/hexane (1:4) to ethyl acetate/hexane (1:1) afforded 25 g of the title compound in its triphenylmethyl-protected form. The triphenylmethyl protecting group was removed by refluxing in methanol (280 mL) containing 10% aqueous citric acid (28 mL) for 4 hours. The reaction mixture was diluted with water (100 mL) and the milky solution extracted with several times with hexane The aqueous layer was extracted with ethyl acetate and the combined organic layers extracted with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was recrystallized using Hexane/ethyl acetate(1:1) to afford 13.4 g of the title compound. MS (FAB, thioglycerol) 564(M+1), mp 135°-137° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1.Br[CH2:23][C:24]1[CH:37]=[CH:36][C:35]2[C:34](=[O:38])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:39])[C:26]=2[CH:25]=1>CN(C=O)C.C(#N)C>[Br-:10].[CH:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH2:11][N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]([C:25]2[C:26]3[C:27](=[O:39])[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34](=[O:38])[C:35]=3[CH:36]=[CH:37][C:24]=2[CH3:23])[CH:4]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Clc1nc[nH]c1Cl
Reactant: O=C1c2ccccc2C(=O)c2cc(CBr)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1-n1c[n+](Cc3ccc4ccccc4c3)c(Cl)c1Cl)C(=O)c1ccccc1C2=O
Product: [Br-]
Temperature: 100 °C

Procedure:
4,5-Dichloroimidazole (1.37 g, 10.0 mmol) and potassium hydroxide (0.61 g, 11.0 mmol) were placed in a round bottom flask and 10 mL acetonitrile was added. The mixture was refluxed for 30 min. The flask was removed from the head and 2-(bromomethyl)naphthalene (2.21, 10.0 mmol) was added. The mixture was returned to heat and refluxed for 2.5 h, during which time a white precipitate formed. The mixture was filtered hot, and upon cooling a precipitate formed in the filtrate. The solid, the mono-substituted imidazole, was collected by a second filtration. This solid (0.28 g, 1.0 mmol) and 2-(bromomethyl)anthraquinone (0.90 g, 3.0 mmol) will be placed in a high-pressure vessel and dissolved in the minimum volume of DMF. The solution will be heated to 100° C. for 8 h. Removal of the volatile components under reduced pressure will yield the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:10]2)=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:17]([O:21][C:22]([N:24]1[CH2:30][CH2:29][C:28](=[O:31])[N:27]([CH2:32][CH2:33][CH2:34][CH2:35][N:13]([CH:9]2[CH2:8][CH2:7][C:6]3[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:10]2)[CH2:14][CH2:15][CH3:16])[CH2:26][CH2:25]1)=[O:23])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCCNC1CCc2ccc(OC)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)N(CCCC=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCN(CCCCN1CCN(C(=O)OC(C)(C)C)CCC1=O)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine prepared as described in Example 1 (800 mg, 3.3 mmol, 1 eq) in 1,2-dichlororethane (40 mL) under inert atmosphere was added 5-oxo-4-(4-oxo-butyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.0 g, 3.6 mmol, 1.1 eq.) in a single portion followed by the sodium triacetoxyborohydride (1.7 g, 8.25 mmol, 2.5 eq.). The reaction was stirred at room temperature for 20 hr, concentrated in-vacuo and then partitioned between 10% KOH (50 mL) and ethyl acetate (100 mL). The organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by silica gel chromatography gave 1.1 g of 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-5-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH2:40])=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]>>[OH:26][CH2:27][C:28]([NH:31][S:32]([C:35]1[S:39][C:38]([NH:40][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:25])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[N:37][CH:36]=1)(=[O:34])=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)(CO)NS(=O)(=O)c1cnc(N)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cnc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 2-amino-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.13) according to general procedure II. Yellow solid. MS (ISP) 589.2 [(M−H)−]; mp 280° C.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2OCC(C)(C)C[O:15]2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([S:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[O:15])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)SCCCc1ccc(C2OCC(C)(C)CO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SCCCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.8 %

Procedure:
Compound 14 (525 mg, 1.70 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (2.0 mL) was added together with a drop of water. The solution was stirred for 15 h at rt. Then aq NaHCO3 (5%, 35 mL) was added and the phases were separated. The organic phase was washed twice with aq NaHCO3 (5%), once with brine and dried (Na2SO4). The solvents were removed under reduced pressure and the oily residue was purified by column chromatography (silica, ether/hexanes, 1:2), affording a yellow oil (279 mg, 74%). IR (neat): {tilde over (v)} 3037, 2928, 2849, 2731, 1693, 1605; 1H NMR δ 1.88–1.99 (m, 2H), 2.35 (s, 3H), 2.78 (t, 3J=7.3 Hz, 2H), 2.89 (t, 3J=7.3 Hz, 2H), 7.35, 7.81 (AA′BB′, 2×2H), 9.98 (s, 1H); 13C NMR (APT) δ 28.1 (+), 30.4 (+), 34.7 (+), 128.8 (−), 129.7 (−), 134.4 (+), 148.3 (+), 191.6 (−), 195.2 (+); GC-MS (EI) obsd 222, 180, 146, 133, 117, 105, 91, 43.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)([OH:17])[CH3:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C>[CH3:1][N:2]1[CH2:25][CH2:24][C:5]2[N:6]([CH2:14][C:15]([O:17][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:16])[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(OC(=O)C(C)(C)C)c2cccnc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
1-(2,8-Dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-2-pyridin-3-yl-propan-2-ol (5.0 g, 14.9 mmol) was dissolved in DMF (100 mL) and sodium hydride (1.8 g, 45 mmol) was added, and the mixture stirred at RT for 15 min. Pivaloyl chloride (3 g, 25 mmol) was added dropwise at the same temperature, and the mixture stirred for 45 min. The reaction was monitored by TLC and LCMS. The reaction mixture was poured into 400 mL ice water to obtain a solid that was filtered. The solid was dissolved in DCM, dried over sodium sulfate and concentrated to obtain the crude product that was purified by column chromatography (silica gel: 100-200 mesh, Eluent: −4-6% MeOH in DCM) to obtain 1.8 g of 2,2-dimethyl-propionic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-1-pyridin-3-yl-ethyl ester. The product was further purified by chiral preparative HPLC to give enantiomers II-16a and II-16b. 1H NMR (CDCl3, Free base): δ (ppm): 8.55 (d, 1H), 8.5 (s, 1H), 7.2 (d, 1H), 7.18 (m, 3H), 6.9 (d, 1H), 4.3 (dd, 2H), 3.65 (d, 1H), 3.52 (d, 1H), 2.65 (m, 2H), 2.5 (m, 2H), 2.5 (s, 3H), 2.4 (s, 3H), 2.3 (d, 1H), 2.0 (s, 3H), 2.0 (m, 1H), 1.2 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:24])=[C:18](N)[CH:19]=[CH:20][C:21]=1Br)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:16]1[CH:21]=[CH:20][C:19]([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:34]=2)=[CH:18][C:17]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1c(Br)ccc(N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Temperature: 80 °C

Procedure:
A mixture of the product of Example 60A (380 mg, 1.23 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (380 mg, 1.23 mmol) and sodium carbonate (391 mg, 3.69 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was degassed and heated at 80° C. for 16 hours. After cooling to ambient temperature and concentration, the residue was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate (3×35 mL). The combined organic phase was washed with saturated brine, dried over sodium carbonate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with 8/1 petroleum/ethyl acetate to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.Br[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[N:6]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:5](=[O:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1CCc1ccc([N+](=O)[O-])cc1
Temperature: 70 °C
Yield: 46.9 %

Procedure:
2-Methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one (1 g, 4 mmol) and 1-(2-bromo-ethyl)-4-nitro-benzene (919 mg, 4 mmol) and potassium carbonate (669 mg, 4.8 mmol) are dissolved in 12 mL acetone and the reaction mixture is heated at 70° C. for 5 min in the microwave oven (Biotage Initiator) and again heated for 5 min at 120° C. The mixture is cooled to room temperature, filtered and the filtrate evaporated to yield the crude product which is subjected to flash chromatography. ISCO Companion CombiFlash, 80 g silica gel, cyclohexane/ethyl acetate, followed by a second purification step, 40 g silica gel, acetone/cylohexane to yield 2-methyl-3-[2-(4-nitro-phenyl)-ethyl]-5,5-diphenyl-3,5-dihydro-imidazol-4-one (750 mg, 45%). LC/MS at 254 nm; [M+H] 400; Rt 3.391 min.
Reaction SMILES: [N+:1]([C:4]([CH3:9])([CH2:7]O)[CH2:5][OH:6])([O-:3])=[O:2].[CH3:10][NH2:11].[CH2:12]=O>>[CH3:10][N:11]1[CH2:7][C:4]([CH3:9])([N+:1]([O-:3])=[O:2])[CH2:5][O:6][CH2:12]1
Reactant: C=O
Reactant: CC(CO)(CO)[N+](=O)[O-]
Reactant: CN
Product: CN1COCC(C)([N+](=O)[O-])C1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a solution of 2-nitro-2-methyl-1,3-propanediol (20.4 g, 151 mmol) in 40% aqueous methylamine (11.7 g, 151 mmol), was added an aqueous solution of formaldehyde (37% formaldehyde, 12.2 g, 151 mmol). The reaction was stirred at room temperature for one week, then extracted with ether three times. The organic fractions were dried over sodium sulfate and concentrated under reduced pressure to give a crude oil which was purified by column chromatography (50 to 100% ethyl acetate in hexanes) to give the desired product (15.4 g, 96.1 mmol, 63%). 1H NMR (400 MHz, CDCl3) δ 1.45 (s, 3H), 2.32 (s, 3H), 2.63-2.66 (d, J=13.2 Hz, 1H), 3.51-3.54 (d, J=12.6 Hz, 1H), 3.67-3.71 (dt, J=1.9, 13.2 Hz, 1H), 3.86-3.89 (d, J=8.5 Hz, 1H), 4.29-4.32 (dd, J=1.2, 8.6 Hz, 1H), 4.61-4.66 (dd, J=2.4, 12.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 22.0, 39.9, 59.8, 71.2, 83.1, 86.1. LRMS (ESI/APCI) m/z 161 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10](=O)[CH2:11][CH2:12][C:13]([C:15]2[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=2)=O)=[CH:7][CH:6]=1)=[O:4].C1(C)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[NH:9][C:8]([C:10]2[S:41][C:13]([C:15]3[NH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc(C(=O)OC)[nH]2)[nH]1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(-c3ccc(C(=O)OC)[nH]3)s2)[nH]1
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A mixture of compound 4 (1.73 g, 5.2 mmol), dry toluene (75 mL), and Lawesson's reagent (1.50 g, 3.7 mmol) was refluxed under an argon atmosphere for 12 hours. The solution was cooled to room temperature and concentrated to one-third its original volume in vacuo. Methanol was added slowly to the toluene until a precipitate appeared. Column chromatography was performed using pure CH2Cl2 (silica gel; 230-400 mesh) as the initial eluant to remove impurities. Conversion to a 50:50 hexanes:EtOAc eluant system yielded 0.86 g (2.6 mmol, 50%) of a yellow solid. 1H-NMR (CDCl3): δ 7.70 (s, 1H), 6.96 (dd, 1H), 6.52 (dd, 1H), 3.93 (s, 3H). 13C-NMR: δ 161.8, 134.0, 132.4, 125.7, 124.0, 117.8, 109.2, 52.2.
Reaction SMILES: Br[C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]([O:15][CH3:16])=[O:14])[C:3]=1[CH3:17].[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>C(COC)OC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:3]1[C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:6][C:2]=1[C:21]1[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=1
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1c(-c2ccccc2)[nH]c(Br)c1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1c(-c2ccccc2)[nH]c(-c2ccncc2)c1C
Yield: 45.5 %

Procedure:
A mixture of methyl 5-bromo-4-methyl-2-phenylpyrrole-3-carboxylate (82 mg, 0.278 mmol), 4-pyridylboronic acid (68 mg, 0.556 mmol), PdCl2(PPh3)2 (20 mg, 0.0278 mmol), and saturated aqueous NaHCO3 (0.3 mL) in dimethoxyethane (1.5 mL) was refluxed for 16 hours. The mixture was extracted with CH2Cl2 (10 mL×3), the combined organic layer dried over Na2SO4, and concentrated ini vacito. The residue was purified by PTLC (1 mm) with acetone-hexane (1:2) to afford the title compound (37 mg, 46% yield).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.Cl>[CH3:11][O:10][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([O:1][CH2:21][O:22][CH3:23])[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(O)c1C=O
Reactant: COCCl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(OC)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
2-Hydroxy-6-methoxybenzaldehyde (200 mg, 1.31 mmol) was placed in a 20 mL reaction vessel, and dissolved in 3.9 mL of dry dichloromethane. To the solution were added N,N-diisopropylethylamine (0.70 mL, 4.0 mmol), 4-dimethylaminopyridine (20 mg, 0.16 mmol), and chloromethyl methyl ether (250 μL, 3.28 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with 70 mL of ethyl acetate and 15 mL of 1N HCl, and extracted. The extract was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound as a pale yellow oil (224.4 mg, 87%).