Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1.N1C=CC=CC=1.[S:31](Cl)(=[O:34])(=[O:33])[NH2:32].C([O-])(O)=O.[Na+].[OH-].[Na+].Cl>CC(N(C)C)=O.CCO.O>[NH2:24][C:23]1[C:3]2[C:4]([O:5][CH2:6][C@H:7]3[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:8]3)=[CH:20][CH:21]=[CH:22][C:2]=2[NH:1][S:31](=[O:34])(=[O:33])[N:32]=1
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](COc2cccc3c2C(N)=NS(=O)(=O)N3)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 3-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 2c, 11.0 g, 33.2 mmol) in DMA (100 mL) was added pyridine (13.4 mL, 166 mmol) and sulfamoyl chloride (7.64 g, 66.4 mmol) in small portions. The mixture was stirred at room temperature under nitrogen for 1 hour until the reaction was complete according to LCMS. Saturated NaHCO3 was added until the mixture was neutral and the solution was extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated. The residue was diluted with EtOH (100 mL) and NaOH (66.4 mL, 132.8 mmol, 2M solution) was added and the solution was heated to 80° C. for 3 hours. The reaction mixture was then allowed to cool to room temperature. The solution was further cool to 0° C. and neutralized with 2N HCl. Water was added and the desired product crashed out. The product was then filtered off and dried to yield the title compound (7.0 g, 51.4%). (M+H)-Boc=311.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.O.[Pt]=O>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([N:17]2[C:11]3[N:10]=[C:9]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=4[Cl:34])[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]=3[CH:15]=[N:16]2)=[CH:19][CH:20]=1
Reactant: O=c1c2cnn(-c3ccc([N+](=O)[O-])cc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)nc32)cc1
Reaction time: 1 h

Procedure:
5-(4-Chloro-phenyl)-6-(2,4-dichloro-phenyl)-1-(4-nitro-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (100 mg, 0.195 mmol) is dissolved in 20 mL of dioxane. Platinumoxide (11.0 mg, 0.0484 mmol) was added as a slurry in 2 mL of water to the reaction mixture under a nitrogen atmosphere. The mixture was placed under balloon pressure of hydrogen and the reaction is completed within 1 h. The solids are filtered off and the solution is concentrated. Purification by reverse phase HPLC affords the title compound. 1H NMR (DMSO, 400 MHz) δ 8.78 (s, 1H), 8.15 (d, 2H), 7.97-7.95 (m, 2H), 7.90 (m, 3H), 7.84 (dd, 1H), 7.78 (m, 1H), 7.30 (d, 2H), 6.00 (s, 2H). HPLC-MS calculated for C23H14Cl3N5O (M+H+) 482.0. Found: 482.0.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:23]([O:25][C:26](C)(C)[CH3:27])=[O:24])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][C:19](C)(C)[CH3:20])=[O:17])=O)(C)(C)C.S(Cl)(Cl)=O>C(O)C>[NH2:8][C@@:9]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)CC(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](N)(C(=O)OCC)[C@@H]21
Yield: 88.7 %

Procedure:
Charge a 500 mL three neck flask equipped with a condenser, nitrogen inlet and a thermometer with ditert-butyl (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (15 g, 36.4 mmol) in ethanol (365 mL). Add thionyl chloride (13.3 mL, 182.3 mmol) to a stirring solution at room temperature via syringe (small exotherm) then heat to reflux. After 24 hours cool the reaction to room temperature and concentrate in vacuo. Dissolve the residue in dichloromethane (50 mL) then concentrate on a rotary evaporator (repeat 3 times). Partition the residue between ethyl acetate (200 mL) and saturated sodium hydrogenate carbonate (150 mL). Wash the organic phase with brine (150 mL), dry over sodium sulfate, filter then concentrate to dryness to give the title compound as an oil (8.24 g, 32.3 mmol). MS (m/z): 256 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[N:3][CH:2]=1.[NH4+:9].[Cl-]>>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[NH:9])[NH2:8])=[N:3][CH:2]=1
Reactant: N#Cc1ccncn1
Reactant: [NH4+]
Agent: [Cl-]
Product: N=C(N)c1ccncn1
Reaction time: 0.17 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of Na (0.11 g) in methanol (100 mL). The mixture was stirred for 10 min. This was followed by the addition of pyrimidine-4-carbonitrile (10 g, 95.15 mmol, 1.00 equiv). The solution was stirred for 2 h at room temperature. To this was added NH4Cl (11 g, 205.65 mmol, 2.16 equiv). The resulting solution was stirred for 4 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of ethanol. The mixture was stirred for 10 min under reflux. The solids were filtered out. The filtrate was concentrated under vacuum. The solids were collected by filtration. This resulted in 5 g (33%) of pyrimidine-4-carboximidamide hydrochloride as a white solid. MS (ESI) m/z 123 ([M+H]+).
Reaction SMILES: CO.O=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>CCCCCCC>[C:15]1([C@@H:21]([NH:23][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCCCCCC
Solvent: CO
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1

Procedure:
In an additional embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of a catalyst, ytterbium trifluoromethanesulfonate, and heptane to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). The next step is reduction of the amine (8) with sodium acetoxyborohydride in the presence of a acetonitrile produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 1. The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium t-butoxide to afford trans-cyclohexane derivative (10) as a major diastereomer. Reduction of the ester functionality in compound (10), using lithium borohydride yields (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) in good overall yield, which is subsequently purified by chromatography.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([OH:31])/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([O:15]C3CCCCO3)[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]1=2>C(O)(=O)C.O.C1COCC1>[S:1]1[C:5]([C@H:6]([OH:31])/[CH:7]=[CH:8]/[C@H:9]2[C:13](=[CH2:14])[CH2:12][C@H:11]([OH:15])[C@@H:10]2[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]1=2
Reactant: C=C1C[C@H](OC2CCCCO2)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: C=C1C[C@H](O)[C@H](C/C=C\CCCC(=O)O)[C@H]1/C=C/[C@@H](O)c1cc2ccccc2s1
Temperature: 25 °C

Procedure:
(Z)-7-((1R,2R,5S)-2-((R,E)-3-(Benzo[b]thiophen-2-yl)-3-hydroxyprop-1-enyl)-3-methylene-5-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl)hept-5-enoic acid, prepared in Step L, is dissolved in a (4:2:1) solution of acetic acid-water-THF (0.5 M). The solution is stirred for several days at room temperature until the reaction is complete, as judged by TLC. The crude product is purified by flash chromatography on regular silica gel using ethyl acetate-hexane-acetic acid as eluent to afford the title compound 21a.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]([C:14]1[CH:20]=[C:19]([OH:21])[CH:18]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]=1[OH:16])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]1[C:15](=[O:16])[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19]([OH:21])([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])[CH:20]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Reactant: COc1ccccc1Br
Product: COc1ccccc1C1(O)C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1

Procedure:
Using the method described in Example 1, 2-bromo-methoxybenzene is reacted with 2,6-di(t-butyl)hydroquinone to provide 2,6-di(t-butyl)-4-hydroxy-4-(2'-methoxyphenyl)-2,5-cyclohexadienone. This product is dissolved in ethanol and reduced with hydrogen gas on a Parr apparatus using palladium on charcoal as the catalyst. The white solid product is recrystallized from benzene to provide 2,6-di(t-butyl)-4-(2'-methoxyphenyl)phenol, m.p. 98.5°-100° C.
Reaction SMILES: [C:1](O)(=[O:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33](=[O:56])[C@@H:34]([NH:43][C:44]([C:46]2[NH:55][C:49]3=[CH:50][N:51]=[C:52]([Cl:54])[CH:53]=[C:48]3[CH:47]=2)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([NH:26][CH:27]1[CH2:28][CH2:29][N:30]([C:33](=[O:56])[C@@H:34]([NH:43][C:44]([C:46]2[NH:55][C:49]3=[CH:50][N:51]=[C:52]([Cl:54])[CH:53]=[C:48]3[CH:47]=2)=[O:45])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[CH2:31][CH2:32]1)(=[O:3])[CH3:2]
Reactant: NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Reactant: CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of acetic acid (7.5 μL, 0.13 mmol) in DMF (5 mL) was added EDCI (33 mg, 0.17 mmol), HOBt (19.5 mg, 0.14 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [2-(4-aminopiperidin-1-yl)-1-(S)-(4-fluorobenzyl)-2-oxoethyl]amide (EXAMPLE 180, 70 mg, 0.16 mmol) and DIPEA (57 μL, 0.33 mmol), and the reaction stirred at rt for 16 h. Solvent was removed in vacuo then crude material partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was washed with NaHCO3 (2×20 mL) and brine (2×30 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (95:5) as the eluent gave the title compound as an off-white powder. m/z (ES+)=486.27 [M+H]+; RT=3.16 min.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C(OCC)C.N([O-])=O.[Na+].[I-:20].[K+]>O>[Cl:10][C:4]1[CH:3]=[C:2]([I:20])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(N)cc1Cl
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (30.5 g, 0.2 mol) in 1:1 diethyl ether/3M HCl (600 mL) at 0° C. was treated dropwise over 15 minutes with a solution of sodium nitrite (18 g, 0.26 mol) in water (100 mL), stirred 15 minutes, then treated with a solution of potassium iodide (50 g, 0.3 mol) in water (50 mL) dropwise over 45 minutes, warmed to room temperature, and stirred for 1.5 hours. The organic phase was washed with water (3×100 mL) and the combined aqueous layers were extracted with diethyl ether. The combined organic layers were combined, washed sequentially with saturated NaHCO3, 25% Na2S2O3, and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 19:1/hexanes:ethyl acetate, triturated in hexanes, filtered, and dried to provide the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]([NH:12][C:13]2[O:14][C:15]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[O:11])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH2:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH3:24]>>[C:8]([C:6]1[CH:5]=[C:4]([C:10]([NH:12][C:13]2[O:14][C:15]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[N:16][N:17]=2)=[O:11])[CH:3]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([C:28]3[CH:27]=[CH:26][C:25]([CH2:23][CH3:24])=[CH:30][CH:29]=3)=[CH:32][CH:33]=2)[CH:7]=1)#[N:9]
Reactant: N#Cc1cc(Br)cc(C(=O)Nc2nnc(-c3ccco3)o2)c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cc(C#N)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 3-bromo-5-cyano-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 41 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>C1COCC1>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)c(OC)c1
Reaction time: 1 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)thiazol-2-amine (0.546 g, 2.182 mmol) in THF (7 mL) was cooled in a dry ice-acetone bath for 5 minutes. Lithium bis(trimethylsilyl)amide (1M in THF) (2.381 ml, 2.381 mmol) was added dropwise, then the flask was removed from the cooling bath for 5 min. The flask was again cooled into a dry ice-acetone bath for 20 min, resulting in the formation of a thick slurry. A suspension of 1-chloroisoquinoline-6-sulfonyl chloride (0.520 g, 1.984 mmol) in THF (5 mL) was added dropwise, then the cooling bath was removed. The reaction was stirred for one hour. The reaction was quenched with saturated ammonium chloride solution, diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The filtrate was purified by silica gel chromatography on a 40 g silica column with 0 to 30% EtOAc/Heptane. The product containing fractions were combined and concentrated to afford a white solid. The solid was triturated with methanol and stirred for five minutes. The solution was filtered and the solids were washed with methanol. The solids were dried under a vacuum to afford 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. m/z (ESI) 498.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([O:29][Si](C(C)C)(C(C)C)C(C)C)[C@H:14]([CH3:40])[O:13][C:12]1=[O:41])[CH2:8][O:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:1]([O:5][C:6](=[O:42])[N:7]([C@H:11]1[CH2:19][CH2:18][CH2:17][C@H:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[C@@H:15]([OH:29])[C@H:14]([CH3:40])[O:13][C:12]1=[O:41])[CH2:8][O:9][CH3:10])([CH3:3])([CH3:2])[CH3:4]
Reactant: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@H](C)OC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COCN(C(=O)OC(C)(C)C)[C@H]1CCC[C@H](Cc2ccc(OC)cc2)[C@@H](O)[C@H](C)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a round bottom flask were added tert-butyl((3S,7R,8R,9S)-7-(4-methoxybenzyl)-9-methyl-2-oxo-8-((triisopropylsilyl)oxy)oxonan-3-yl)(methoxymethyl)carbamate (1.61 g, 2.65 mmol), THF (26.5 ml) and TBAF (1.0 M, 5.30 ml, 5.30 mmol) at room temperature and an exotherm noted. The reaction was stirred at room temperature until thin layer chromatography (TLC) showed complete consumption of starting material. After approximately 2 h, the reaction was quenched by the addition of NaHCO3 and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over MgSO4, concentrated, and purified by column chromatography on SiO2 (0→10%, hold, 10→20%, hold, 20→50% hold EtOAc/hexanes gradient) to furnish the title product as a colorless oil (703 mg, 59%): IR (neat) 3479, 2976, 2936, 1744, 1700, 1512, 1368, 1297, 1246, 1175 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.15-7.06 (m, 2H), 6.87-6.79 (m, 2H), 4.96-4.87 (m, 1H), 4.85-4.73 (m, 2H), 4.61-4.49 (m, 1H), 4.23-4.18 (m, 1H), 3.79 (s, 3H), 3.51 (td, J=8.8, 5.8 Hz, 1H), 3.32 (d, J=12.9 Hz, 3H), 3.01 (dd, J=13.6, 4.9 Hz, 1H), 2.44 (dd, J=16.2, 7.3 Hz, 1H), 2.07 (d, J=16.5 Hz, 1H), 1.69 (s, 2H), 1.63-1.49 (m, 3H), 1.44 (d, J=5.9 Hz, 9H), 1.40 (d, J=6.3 Hz, 3H), 0.94 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 173.45, 158.00, 129.72, 113.97, 76.28, 55.25, 37.08, 28.24, 27.29, 19.43, 18.18 (Note: Peaks missing, likely due to rotamers); HRMS-ESI (m/z) ([M]+) calcd for C24H37NO7, 451.2558; found, 451.257.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH2:47]I>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:47][C:46]2[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: COc1ccc(CI)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)cc1OC

Procedure:
In analogy with Example 44c), 1 g of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] in 4 ml of abs. THF is deprotonated (-75° C.) with 6.42 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF, with the addition of 0.66 ml of DMPU, and alkylated with 911 mg of 3,4-dimethoxybenzyl iodide. Chromatography on silica gel (eluents D, C and J) gives the pure title compound. TLC Rf (C)=0.42. MS M+ =455.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:14]=[C:13]2[C:7]([N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][NH:12]2)=[CH:6][N:5]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([CH3:24])[S:22][CH:23]=1>CC(N(C)C)=O>[Cl:3][C:4]1[N:14]=[C:13]2[C:7]([N:8]([CH3:16])[C:9](=[O:15])[CH2:10][CH2:11][N:12]2[CH2:18][C:19]2[N:20]=[C:21]([CH3:24])[S:22][CH:23]=2)=[CH:6][N:5]=1
Reactant: CN1C(=O)CCNc2nc(Cl)ncc21
Reactant: Cc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc(CN2CCC(=O)N(C)c3cnc(Cl)nc32)cs1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a cooled (ice/water bath) suspension of sodium hydride (60% dispersion in mineral oil; 13 mg, 0.38 mmol) in DMA (0.5 mL) was added a solution of 10-chloro-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 100; 63 mg, 0.30 mmol) in DMA (1 mL). The reaction mixture was allowed to stir, under nitrogen, in ice bath for 10 minutes prior to addition of 4-chloromethyl-2-methylthiazole (ASDI; 75 mg, 0.51 mmol). The reaction mixture was stirred in an ice bath for 20 minutes and then warmed to ambient temperature over 1 hour.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[C:25]1([NH:31][C:32]([C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([C:32]([NH:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:33])[CH:35]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(Br)c3c(N)ncnn23)CC1
Reactant: O=C(Nc1ccccc1)c1cccc(B(O)O)c1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3cccc(C(=O)Nc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 96 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 330 and using tert-butyl 4-{4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl}piperidine-1-carboxylate and (3-phenylaminocarbonylphenyl)boronic acid as starting material, 334 mg (96%) of the desired product was isolated. LC-MS m/z [M+H]+ 513.2, RT 3.13 min.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[CH:23][CH:24]=[O:25])=[CH:9][CH:8]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=Cc1ccc(-c2cncnc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1ccc(-c2cncnc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(5-pyrimidinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 211 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[Sn](Cl)Cl>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(N)cc2)cn1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
A mixture of 1-(4-nitrophenyl)imidazole-4-carboxylic acid ethyl ester (see part (i)) (950 mg, 3.64 mmol) and tin (II) chloride (4.11 g, 18.2 mmol) in absolute ethanol (30 ml) was heated under reflux for 30 minutes under nitrogen. After cooling to room temperature the mixture was concentrated under reduced pressure and then partitioned between ethyl acetate (30 ml) and saturated sodium hydrogen carbonate solution (20 ml). The aqueous layer was extracted with ethyl acetate (30 ml) and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 1-(4-aminophenyl)imidazole-4-carboxylic acid ethyl ester (810 mg, 96%) as a yellow oil.