Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:39]([CH2:40]C)=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:42]C)=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:44][CH3:45])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:35]([CH3:42])=[CH:36][CH:37]=[CH:38][C:39]=4[CH3:40])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:44][CH3:45])[CH2:12][CH2:11]1
Reactant: CCc1cccc(CC)c1NC(=O)Nc1ncnc2cc(OCCCN3CCC(CNC(=O)OC(C)(C)C)CC3)c(OC)cc12
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(NC(=O)Nc3c(C)cccc3C)ncnc2cc1OCCCN1CCC(CN)CC1

Procedure:
Using an analogous procedure to that described in Example 21, 1-{7-[3-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}-3-(2,6-diethylphenyl)urea was reacted with trifluoroacetic acid to give the title compound; NMR Spectrum: (DMSOd6) 1.0-2.0 (m, 9H), 2.23 (s, 6H), 2.4 (m, 2H), 2.7-2.9 (m, 4H), 3.1-3.5 (partially obscured by a water signal), 3.93 (s, 3H), 4.18 (t, 2H), 6.9-7.15 (m, 4H), 7.23 (s, 1H), 8.03 (s, 1H), 8.62 (s, 1H), 11.7 (s, 1H); Mass Spectrum: M+H+ 493.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][CH2:8][C:9]([C:12](OC)=[O:13])=[C:10]([CH3:11])[C:4]=2[CH:3]=1.CC(C[AlH]CC(C)C)C.C1COCC1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][CH2:7][CH2:8][C:9]([CH2:12][OH:13])=[C:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: COC(=O)C1=C(C)c2cc(Br)ccc2OCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC1=C(CO)CCOc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a stirred solution of methyl 7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepine-4-carboxylate from step H5 (2.0 g, 6.73 mmol), in THF (75 mL) was added DIBAL-H/THF (1.0 M, 67.3 mL, 67.3 mmol) at −60° C. The mixture was allowed to warm to rt over 3 h. The reaction was chilled to −78° C. and additional DIBAL-H in THF (5.0 equivalents) was added. The reaction was again allowed to warm to rt over 3 h. After an additional 20 h, the reaction mixture was carefully quenched with water. The aqueous mixture was extracted with diethyl ether. The organic layer was concentrated in vacuo. The residue was purified by silica-gel column chromatography (hexanes-50% EtOAc) to give (7-bromo-5-methyl-2,3-dihydrobenzo[b]oxepin-4-yl)methanol (1.53 g, 5.68 mmol, 84% yield). MS (M+H-water)+=251.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>CCO>[C:5]1([C@H:8]2[CH2:9][CH2:10][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][CH2:13]2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(Cl)cc2)CC1
Solvent: CCO
Product: COC(=O)[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 16 h

Procedure:
10% Palldium on carbon (1800 mg) was added to a solution of methyl trans-4-(4-chlorophenyl)cyclohexanecarboxylate (8670 mg) in EtOH (100 mL). The resulting suspension was stirred for 16 h under an atmosphere of hydrogen at 25 bar in a high pressure cell then was filtered through diatomaceous earth and concentrated in vacuo to give the title compound (6940 mg) as a solid; 1H NMR δ 7.30-7.11 (5H, m), 3.59 (3H, s), 2.53-2.30 (2H+ DMSO, m), 1.98 (2H, m), 1.82 (2H, m), 1.47 (4H, m); MS m/e M.+ 218.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH:12]([Br:17])[CH:13]3O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>CCOCC>[C:1]1([C:7]2[CH:15]=[C:14]3[C:10](=[CH:9][CH:8]=2)[CH2:11][C:12]([Br:17])=[CH:13]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1c2cc(-c3ccccc3)ccc2CC1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: BrC1=Cc2cc(-c3ccccc3)ccc2C1
Yield: 79.3 %

Procedure:
To a one-necked flask of 500 ml, fitted with an dropping funnel and on top of the funnel a condenser, was added 10.19 g (35.2 mmol) of 6-phenyl-2-bromoindanol, 0.671 g (0.10 mol %) p-toluenesulfonic acid and 350 ml of toluene. After 7 hours of refluxing the mixture was diluted with ether and extracted with water and water/NaHCO3. The organic layer was dried over Na2SO4. The Na2SO4 was filtered off and the filtrate was evaporated under reduced pressure. The solid material was dissolved in hot n-pentane and recrystallized giving 7.56 g (27.9 mmol) of 5-phenyl-2-bromoindene. Yield 79%.
Reaction SMILES: F[C@H]1CN(C2C=CC(CC3C=CC=CC=3C)=CC=2)[C@H]([CH2:21][C:22]([O:24][CH3:25])=[O:23])C1.[C:26]([Cl:29])(=O)C.[ClH:30].C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl>[ClH:29].[CH3:22][OH:23].[CH2:26]([Cl:29])[Cl:30].[CH3:25][O:24][C:22]([CH3:21])=[O:23]
Reactant: COC(=O)C[C@@H]1C[C@@H](F)CN1c1ccc(Cc2ccccc2C)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
methyl 2-((2R,4R)-4-fluoro-1-(4-(2-methylbenzyl)phenyl)pyrrolidin-2-yl)acetate: A ˜3 M solution of HCl/MeOH/CH2Cl2/MeOAc was prepared by addition of acetyl chloride (0.64 mL) to a 1:1 solution of MeOH/CH2Cl2 (2.4 mL) at 0° C. The resulting solution of HCl was added to 37C (0.0051 g, 0.017 mmol). After stirring at rt for 2 h, the reaction was basified with sat. Na2CO3 (aq) and the desired product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography to provide 37D (yellow oil, 0.0021 g, 6.2 mmol, 37% yield). LC-MS Anal. Calc'd for C21H24FNO2 341.42. found [M+H] 342.0. 1H NMR (400 MHz, chloroform-d) δ ppm 7.14 (3 H, q, J=4.77 Hz), 7.07-7.11 (1 H, m), 7.01 (2 H, d, J=8.25 Hz), 6.56 (2 H, d, J=8.25 Hz), 5.30 (1 H, d, J=53.34 Hz), 4.29-4.38 (1 H, m), 3.89 (2 H, s), 3.67-3.69 (1 H, m), 3.63-3.75 (3 H, m), 3.50-3.61 (1 H, m), 2.99 (1 H, dd, J=15.40, 2.75 Hz), 2.54-2.68 (1 H, m), 2.25 (3 H, s), 2.17 (2 H, dd, J=15.40, 9.90 Hz).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][C:12]=2[F:20])[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][C:46]1[C:47](=[O:59])[N:48]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)[CH:49]=[CH:50][CH:51]=1.CCN(CCO)CC>CN(C=O)C.CO>[F:20][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[NH:45][C:46]2[C:47](=[O:59])[N:48]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[CH:49]=[CH:50][CH:51]=2)[CH:18]=[CH:19][C:11]=1[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: NC(=O)c1cc(Oc2ccc(C(=O)O)cc2F)ccn1
Reactant: Nc1cccn(-c2ccc(F)cc2)c1=O
Agent: CCN(CC)CCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)c1cc(Oc2ccc(C(=O)Nc3cccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
To a solution of 4-(2-carbamoylpyridin-4-yloxy)-3-fluorobenzoic acid (0.3 mmol, 83 mg) in DMF (2 mL), were added HATU (Perspective Biosystems, 0.45 mmol, 171 mg), 3-amino-1-(4-fluorophenyl)pyridin-2(1H)-one (0.3 mmol, 61.2 mg) and DEEA (Aldrich, 0.2 mL). The reaction mixture were heated at 50° C. for 5 h. After cooling to room temperature, 5 mL of methanol was added. The product was purified by preparative HPLC. The desired fractions were combined, neutralized to pH 7-8 with aq. K2HPO4, and concentrated in vacuo. The precipitate that formed was collected by filtration, rinsed with water, and dried under vacuum to give the desired product (78 mg, 57% yield). MS(ESf+) m/z 463.25 (M+H)+.
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1>C(O)(C)C.[OH-].[Na+]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]#[C:15][CH2:14][O:2][C:3]2[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:10])=[O:11])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(C#CCBr)cc1
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=S(=O)(O)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Yield: 71.6 %

Procedure:
To a solution of 4-hydroxybenzenesulfonic acid sodium salt (2.81 g, 12.11 mmol) in 50 mL of isopropyl alcohol, 11.8 mL 2N NaOH and 5.56 g (24.2 mmol, 2 eq) of 1-(3-bromo-prop-1-ynyl)-4-chloro-benzene was added. The solution was heated to 70° C. overnight. The reaction was cooled, concentrated in vacuo, filtered and air dried to afford 2.8 g (67%) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonic acid, sodium salt. Electrospray Mass Spec 321.3 (M−H)−.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH:18][C:19](=[O:27])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:16][C:15]([C:28](=[O:33])[NH:29][CH:30]3[CH2:32][CH2:31]3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)C.O1CCCC1.CO.[OH-].[Li+]>O>[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([CH2:5][C:4]([OH:34])=[O:3])[CH2:7][CH2:8]2)=[N:13][CH:14]=[C:15]([C:28](=[O:33])[NH:29][CH:30]2[CH2:31][CH2:32]2)[CH:16]=1)=[O:27]
Reactant: CCOC(=O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2NC(=O)c2cccc(Cl)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCN(c2ncc(C(=O)NC3CC3)cc2NC(=O)c2cccc(Cl)c2)CC1
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 0.23 g (0.47 mmol) of [3′-(3-chloro-benzoylamino)-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester in a 5:2 mixture of tetrahydrofuran:methanol is added a solution of 0.056 g (2.3 mmol) of lithium hydroxide in water (1 mL). The reaction mixture is stirred overnight and then concentrated under reduced pressure to remove volatile organics. The pH of the mixture is adjusted to approximately pH 2 by the addition of concentrated hydrochloric acid causing a solid to precipitate. The formed colorless solid is collected by filtration and dried under vacuum to provide 0.14 g (66%) of [3′-(3-chloro-benzoylamino)-5′-cyclopropylcarbamoyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]=[CH:2][CH2:3][NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)[N:8]=[C:7]([C:21]#[N:22])[N:6]=1
Reactant: N#Cc1nc(NCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1nc(NCC=O)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 67.3 %

Procedure:
To a stirring solution of 4-(2-hydroxy-ethylamino)-6-(3-trifluoromethyl-phenyl)-pyrimidine-2-carbonitrile (308 mg) in dichloromethane (5 ml) was added Dess-Martin periodinane (424 mg) and the resulting suspension was stirred at room temperature for 45 mins. Reaction mixture was diluted with dichloromethane (50 ml) and washed with water (3×50 ml), brine (50 ml), dried over MgSO4 and concentrated in vacuo. The residue was filtered through silica gel pad using heptane and ethyl acetate (1:1) as eluant, solvent was removed in vacuo to give 4-(2-oxo-ethylamino)-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a white solid (206 mg) MS m/z: 307.5 (M+1).
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][O:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][Mg]Cl>C1COCC1>[O:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([CH3:13])([OH:3])[CH3:2])[C:12]=2[O:11][CH2:10]1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1cccc2c1OCO2
Solvent: C1CCOC1
Product: CC(C)(O)c1cccc2c1OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
25.5 g of 4-acetylbenzo[1,3]dioxole is mixed with 57.2 ml of methylmagnesium chloride solution (3M in THF) in 375 ml of THF at room temperature under argon. It is stirred for 16 hours at room temperature and added to ice/2H hydrochloric acid. It is extracted with ethyl acetate, and the organic phase is washed with water and brine, and it is dried (Na2SO4). 27.89 g of 1-[benzo(1,3)dioxol-4-yl]-1-methylethanol is obtained as a brown oil
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9]O)=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.S(Cl)([Cl:19])=O>>[ClH:1].[Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][Cl:19])=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc(Cl)cc(OC2CCCC2)c1CO
Reactant: O=S(Cl)Cl
Product: Cc1nc(Cl)cc(OC2CCCC2)c1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (6-chloro-4-cyclopentoxy-2-methyl-pyridin-3-yl)-methanol (3.5 g, 14.5 mmol), a solution of thionyl chloride (2.0 M solution in methylene chloride, 72 mL, 144 mmol) is added, and the mixture is stirred for 2 hours at ambient temperature. All volatiles are removed in vacuo to afford 6-chloro-3-chloromethyl-4-cyclopentyloxy-2-methyl-pyridine hydrochloride salt as a white powder.
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([CH:19]=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:31]C1C2C(=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)N=C(C2C=CC=CC=2)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:15]3[CH:24]=[C:23]4[C:18]([C:19]([CH3:31])=[CH:20][C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:22]4)=[CH:17][CH:16]=3)[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Reactant: Cc1cc(-c2ccccc2)nc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc(-c2ccccc2)nc2cc(-c3nc(C4CCC4)n4ncnc(N)c34)ccc12

Procedure:
7-Cyclobutyl-5-(4-methyl-2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine was prepared using the same procedures described for 7-cyclobutyl-5-(2-phenyl-quinolin-7-yl)-imidazo[5,1-f][1,2,4]triazin-4-ylamine, except 4-methyl-2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline was used in place of 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline and 2 equivalents of cesium carbonate was used in place of 3 equivalents of sodium carbonate; 1H NMR (CDCl3, 400 MHz) δ 2.06 (m, 1H), 2.17 (m, 1H); 2.47-2.52 (m, 2H); 2.67-2.72 (m, 2H); 2.82 (d, J=0.8 Hz, 3H); 4.14-4.25 (m, 1H); 5.78 (brs, 2H); 7.46-7.56 (m, 3H); 7.77 (d, J=0.8 Hz, 1H); 7.92 (s, 1H); 7.98 (dd, J=8.6, 1.8 Hz, 1H); 8.15-8.18 (m, 3H); 8.39 (d, J=1.6 Hz, 1H); MS (ES+): m/z 407.03 (100) [MH+], HPLC: tR=3.54 min (MicromassZQ, polar—5 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][C:19]([CH3:22])([CH3:21])[NH:18][C:17]([CH3:24])([CH3:23])[CH2:16]3)[N:9]=2)=[CH:4][CH:3]=1.[Li]CCCC.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1>C1COCC1.CCC(C)C.C1COCC1>[CH3:30][N:31]1[CH2:36][CH2:35][C:34]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]4)[N:9]=3)=[CH:6][CH:7]=2)([OH:37])[CH2:33][CH2:32]1
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)cc3)n2)CC(C)(C)N1
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCC(C)C
Product: CN1CCC(O)(c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)cc2)CC1
Reaction time: 0.25 h

Procedure:
[4-(4-Bromophenyl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (116 mg; 0.3 mmol) in THF/isopentane (3 ml/0.6 ml) was cooled to −100° C. nBuLi (1.6M in hexane, 0.56 ml; 0.9 mmol) was added within 5 minutes and the reaction mixture stirred for 15 minutes at this temperature. N-methyl-4-piperidone (71 μl, 0.6 mmol) was added in THF (71 μl), the reaction mixture stirred for 10 minutes at −100° C., poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, evaporated to dryness and purified via chromatography on silicagel (EtOAc/MeOH/ammonia:90/9/1 to 80/18/2) to give the title compound as a white solid. Yield: 25 mg (17%).
Reaction SMILES: C[NH:2][C:3](=[O:5])[O-:4].[C:6](OC(=O)C)(=O)C.[N+:13]([O-:16])(O)=[O:14]>C(Cl)(Cl)Cl>[CH3:6][O:4][C:3]([N-:2][N+:13]([O-:16])=[O:14])=[O:5].[NH4+:2]
Reactant: O=[N+]([O-])O
Reactant: CNC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: COC(=O)[N-][N+](=O)[O-]
Product: [NH4+]

Procedure:
Ammonium N(methoxycarbonyl)N-nitroamide (ammonium N-nitromethylcarbamate) was prepared by suspending 1.05 moles of methylcarbamate in 400 ml. of CHCl3 cooled in an ice bath under an argon atmosphere. This suspension was treated with 1 mole of acetic anhydride followed by a slow dropwise addition of 1 mole of 98% HNO3. The reaction temperature got as high as 25° C. with continuous ice bath cooling of the reaction vessel. The reaction mass was stirred overnite and the temperature was allowed to slowly rise to room temperature. To the reaction mixture was added 0.5 L. of chlorobenzene and the reaction mixture was then evaporated down to 300 ml. of total volume in a rotary evaporator. Another 0.5 L. of chlorobenzene and 100 ml. of methanol were added to the reaction mixture to dissolve the precipitated solid N(methoxycarbonyl)N-nitroamide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])(C)(C)C.CC1(C)O[C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=[O:38])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:28]([C:30]4[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=4)[C:33]#[N:34])[CH2:27][C:26](=[O:38])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(Cl)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (3-amino-4′-chloro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G12) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow powder (79 mg).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[CH:13]1([S:16](Cl)(=[O:18])=[O:17])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl.Cl.O>[CH:13]1([S:16]([NH:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=2)(=[O:18])=[O:17])[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CNS(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitrobenzylamine HCl (1.5 g), cyclopropanesulfonyl chloride (1 g) and triethylamine (3 mL) were dissolved in dichloromethane (20 mL). The reaction solution was stirred at rt overnight. The reaction mixture was diluted with 1N HCl aq. solution (50 mL) and water (100 mL). The solution was extracted with ethyl acetate (2×100 mL). The organic solution was evaporated to give N-cyclopropylsulfonyl-4-nitrobenzylamine. 1H NMR (DMSO-d6): δ 0.89 (d, J=7.8 Hz, 4H), 4.33 (d, J=6.6 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.83 (t, J=6.6 Hz, 1H), 8.20 (d, J=8.7 Hz, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(CC)CC>CCO>[CH2:17]([O:16][C:14]([C:13]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH2:5][CH2:4][NH:3][CH:12]=1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NCCc1c[nH]cn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CNCCc2nc[nH]c21
Temperature: 25 °C

Procedure:
A mixture of histamine dihydrochloride (5.52 g, 30 mmol), ethyl bromopyruvate (5.0 mL, 36 mmol), and active carbon (500 mg) in anhydrous EtOH (80 mL) was refluxed under nitrogen for 24 hours. After cooling to room temperature, Et3N (30 mL) was added, and the mixture was refluxed at 90° C. for 6 hours. The active carbon was filtered off, and the filtrate was concentrated in vacuo. The residue was taken up in CHCl3, and washed twice with water, then dried over Na2SO4, and evaporated in vacuo. The residual oil was purified by column chromatography on silica gel eluting with hexane-EtOAc (60:40) to give the title compound as a pale-yellow solid. 1H-NMR (CDCl3): δ 7.49 (1H, d)), 7.00 (1H, s), 6.79 (1H, s), 4.85 (1H, br s), 4.30 (2H, q), 3.38 (2H, m), 3.06 (2H, m), 1.36 (3H, t); MS (ES): 208 (MH+).
Reaction SMILES: OC[C@@H](N[C:11](=[O:26])[C@@:12]([CH3:25])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.S(=O)(=O)(O)[OH:28]>O1CCOCC1>[CH3:25][C@:12]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[CH3:18])[C:11]([OH:26])=[O:28]
Reactant: O=S(=O)(O)O
Reactant: CC(C)(C)CC[C@@](C)(C(=O)N[C@H](CO)c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@](C)(C(=O)O)c1ccccc1
Yield: 98 %

Procedure:
To a solution of Example 49A (3.78 g, 10.7 mmol) in 1,4-dioxane (60 mL) was added 4 M sulfuric acid (60 mL) and the reaction was stirred at reflux for 48 hours. The solution was concentrated in vacuo, dissolved in 1 N NaOH (250 mL), and washed with hexane (200 mL). The aqueous layer was acidified to pH 1 with 6 N HCl and extracted with ethyl acetate (3× 200 mL). The combined ethyl acetate layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give a clear oil (2.47 g, 98%). 1H NMR (300 MHz, CDCl3): δ ppm 0.86 (s, 9H) 1.09 (m, 2H) 1.56 (s, 3H) 1.99 (m, 2H) 7.33 (m, 5H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:69])/[C:30](=[N:56]\[O:57][C:58]3([C:62]([O:64]C(C)(C)C)=[O:63])[CH2:61][CH2:60][CH2:59]3)/[C:31]3[N:32]=[C:33]([NH:36]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:34][CH:35]=3)[C:26](=[O:70])[N:17]2[C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:10])[CH3:9].C1(OC)C=CC=CC=1>CS(C)=O>[C:8]([O:11][CH2:12][C:13]1[CH2:14][S:15][C@@H:16]2[C@H:27]([NH:28][C:29](=[O:69])/[C:30](/[C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:56]\[O:57][C:58]3([C:62]([OH:64])=[O:63])[CH2:59][CH2:60][CH2:61]3)[C:26](=[O:70])[N:17]2[C:18]=1[C:19]([OH:21])=[O:20])(=[O:10])[CH3:9]
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)/C(=N\OC3(C(=O)OC(C)(C)C)CCC3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OC3(C(=O)O)CCC3)c3csc(N)n3)[C@H]2SC1
Yield: 53 %

Procedure:
Trifluoroacetic acid (100 ml) was added to a mixture of the product of Stage (a) (12.5 g) and anisole (5 ml) at 0°. The mixture was treated substantially as described in Example 1 (b) to give the title compound (4 g), λmax (pH 6 buffer) 246 nm (E1 cm1% 264), λinf 295 nm (E1 cm1% 118), [α]D20 +27.3° (c 1.0, DMSO).
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:31])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][N:28]=[N+]=[N-])[O:24][CH2:23]2)[CH:17]([CH:32]([OH:34])[CH3:33])[C:16]3=[O:35])=[O:13])=CC=1)([O-])=O.P([O-])([O-])([O-])=O>[Pd].O1CCOCC1>[NH2:28][CH2:27][CH:25]1[O:24][CH2:23][CH:22]([S:21][C:20]2[CH:19]([CH3:31])[CH:18]3[N:15]([C:16](=[O:35])[CH:17]3[CH:32]([OH:34])[CH3:33])[C:14]=2[C:12]([OH:13])=[O:11])[CH2:26]1
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CN=[N+]=[N-])C3)C(C)C12
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)O)=C(SC3COC(CN)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.320 gof product from Example 63, 0.220 g of 10% palladium/carbon, 12 ml of 0.05Msodium phosphate buffer (pH 7) and 32 ml of dioxane to give 0.112 g of the desired product.