Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][NH:23][CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[CH:11]1([CH2:14][N:15]2[CH2:21][CH2:20][CH:19]3[CH2:22][N:23]([C:2]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:9])[CH2:24][CH2:25][N:18]3[C:17]3[N:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:12][CH2:13]1
Reactant: c1cnc2c(c1)N(CC1CC1)CCC1CNCCN21
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccnc1)N1CCN2c3ncccc3N(CC3CC3)CCC2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nicotinoyl chloride hydrochloride (58.2 mg, 0.317 mmol) was added at room temperature to a solution of the product of Example 74A (82 mg, 0.317 mmol) in CH2Cl2 (4 mL) and triethylamine (0.111 mL, 0.793 mmol). The mixture was stirred at room temperature for 30 minutes and then concentrated under vacuum. The residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 Maqueous (NH4)2CO3-methanol, 40:60-0:100 over 15 minutes) to provide the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.16-0.21 (m, 2H), 0.45-0.54 (m, 2H), 0.93-1.03 (m, 1H), 1.61-1.75 (m, 1H), 1.79-1.91 (m, 1H), 2.90-3.05 (m, 2H), 3.19-3.30 (m, 2H), 3.34-3.50 (m, 4H), 3.54-3.64 (m, 1H), 3.71-3.92 (m, 2H), 6.74 (dd, J=7.8, 4.7 Hz, 1H), 7.00 (dd, J=7.9, 1.5 Hz, 1H), 7.45 (ddd, J=7.9, 4.9, 0.9 Hz, 1H), 7.65 (dd, J=4.6, 1.5 Hz, 1H), 7.83 (ddd, J=8.1, 2.0, 1.8 Hz, 1H), 8.58-8.67 (m, 2H); MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([NH:14][NH2:15])=[O:13])=[CH:5]2.[N:16]([O-])=O.[Na+]>Cl.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([C:12]([N:14]=[N+:15]=[N-:16])=[O:13])=[CH:5]2
Reactant: O=N[O-]
Reactant: NNC(=O)c1cc2cc(F)ccc2cn1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc2cc(F)ccc2cn1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a suspension of 6-fluoro-isoquinoline-3-carboxylic acid hydrazide in HCl (1 N, 50 mL) and water (1 L) was added a solution of NaNO2 (11.4 g, 170 mmol, 1.5 eq) in water (100 mL) dropwise at 0-5° C. The mixture was stirred at 0-5° C. for 1 h. Another solution of NaNO2 (5.7 g, 85 mmol, 0.5 equiv.) in water (30 mL) was added and the reaction was stirred at 0-5° C. for 3 h until LC-MS indicated the completion of the reaction. The precipitate was filtered, washed with cold water, and dried under high vacuum to give 6-fluoro-isoquinoline-3-carbonyl azide as a light yellow solid (21.3 g, 89%). LRMS (M+H+) m/z 217.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[CH:24]2)=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[CH:24]2)=[O:20]
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: CC(C)Cn1ncc2cc(Br)cc(CO)c21
Product: COC(=O)c1ccc2c(cnn2Cc2cc(Br)cc3cnn(CC(C)C)c23)c1
Yield: 65 %

Procedure:
Compound 26 was prepared following general method 3A, using compound 18 as a starting material and 1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 65%.
Reaction SMILES: [C:1](=[O:7])([O-])[O:2][CH2:3][CH2:4]Cl.[CH2:8]1[CH:13]2[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]2[CH2:11][CH2:10][N:9]1[CH2:27][CH2:28][O:29][CH2:30]C(O)=O.C(O)C>C(Cl)(Cl)Cl>[CH2:8]1[CH:13]2[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:12]2[CH2:11][CH2:10][N:9]1[CH2:27][CH2:28][O:29][CH2:30][C:1]([O:2][CH2:3][CH3:4])=[O:7]
Reactant: O=C(O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: O=C([O-])OCCCl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
0.11 g of chloroethyl carbonate was added to a solution of 0.5 g of 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethoxyacetic acid (prepared as described in Example 2) in 10 ml of chloroform containing 2% by volume ethanol, whilst ice-cooling, and the mixture was stirred at room temperature for 1 hour. At the end of this time, it was washed with water, and the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through silica gel eluted with ethyl acetate, to give 0.25 g of the title compound as a colorless oil. The infrared absorption spectrum of this compound is identical with that of the compound prepared as described in Example 1.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[C:7]([CH3:26])[N:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:27]([CH2:29][NH2:30])[OH:28]>>[OH:28][CH2:27][CH2:29][NH:30][C:23](=[O:25])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:12]=[C:11]([C:9]3[CH:8]=[C:7]([CH3:26])[N:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:10]=3)[O:15][N:14]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(-c2nc(-c3ccc(CC(=O)O)cc3)no2)cc(CC(C)C)n1
Reactant: NCCO
Product: Cc1cc(-c2nc(-c3ccc(CC(=O)NCCO)cc3)no2)cc(CC(C)C)n1

Procedure:
N-(2-Hydroxy-ethyl)-2-{4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetamide is prepared from {4-[5-(2-isobutyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-acetic acid and ethanolamine in analogy to Example 65; LC-MS: tR=0.77, [M+1]+=395.19.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](O)(=[C:12]1[C:20](=[O:21])[CH2:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:13]1=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10]>CCO.C(O)(C(F)(F)F)=O>[NH:1]([C:7](=[C:12]1[C:13](=[O:14])[CH2:15][C:16]([CH3:17])([CH3:18])[CH2:19][C:20]1=[O:21])[CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)CC(O)=C1C(=O)CC(C)(C)CC1=O
Reactant: NCCC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)CC(NCCC(=O)O)=C1C(=O)CC(C)(C)CC1=O
Yield: 98 %

Procedure:
To a stirred suspension of H-β-Ala-OH (1.02 g, 11.4 mmol) and ivDde-OH (5 ml, 22.9 mmol) in EtOH was added TFA (88 μL, 1 mmol) at room temperature.1 The mixture was then refluxed for 24 hours. After the solvent was evaporated in vacuo, a crude product was purified by column chromatography with CH3OH/CH2Cl2 (0.1% TFA) gradient to afford ivDde-β-Ala-OH (3.3 g, 97.6%). NMR (CDCl3) δ 1.02 (m, 12H), 1.90-2.03 (m, 1H), 2.39 (s, 4H), 2.75 (t, J=6.0 Hz, 2H), 3.06 (br d, =6.0 Hz, 2H), 3.78 (q, J=6.0 Hz, 2H); 13C NMR (CDCl3) δ 22.8, 28.4, 29.4, 30.2, 34.1, 37.4, 39.6, 52.9, 107.4, 173.0, 177.2; MS (MALDI) m/z: calcd for C16H26NO4 296.2; found 296.5 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Cl)[CH:35]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:40][C:36]5[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=5)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: ClCc1cccnc1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (3.9 g) obtained in Example 2 was suspended in dimethyl sulfoxide (230 ml), and to the suspension was added potassium carbonate (4.0 g), and the mixture was stirred at room temperature for 30 minutes. 3-picolylchloride hydrochloride (1.9 g) was added and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (500 ml), and the precipitated crystals were recovered by filtration to obtain the title compound (2.9 g, 61%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:21][C:22]\2=[O:23])[N:15]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].ClCCl>C(O)C>[C:3]([O:7][C:8]([NH:10][C:11]1[S:12][CH:13]=[C:14](/[CH:16]=[C:17]2\[CH2:18][N:19]([C:24]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21][CH:22]\2[OH:23])[N:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2=O)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)cs1
Temperature: 0 °C

Procedure:
Sodium borohydride (0.27 g) was added to a solution of (E)-3-{[2-(t-butoxycarbonylamino)-1,3-thiazol-4-yl]methylidene}-1-(triphenylmethyl)piperidin-4-one (3.1 g) in a mixed solvent of dichloromethane (15 ml) and ethanol (15 ml), while stirring at 0° C. After being stirred at room temperature for 1.5 hours, the mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure to afford the title compound as a yellow amorphous solid in a quantitative yield.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].O1CCOCC1.[NH4+].[OH-]>C(OCC)C>[C:8]1([Sn:18]([CH3:20])([CH3:19])[CH3:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:7]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Brc1ccc2ccccc2c1
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[Sn](C)(C)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
tert-Butyllithium (12.5 ml, 21.25 mmol, 1.7M in pentane) is added dropwise to a stirred solution of 2-bromonaphthalene (2 g, 9.66 mmol) in anhydrous diethyl ether (40 ml) under argon at -78° C. The solution is stirred for 15 min and then treated with a 2.71M solution of trimethyltin chloride in dioxane (4.63 ml, 12.55 mmol). The heterogeneous mixture is warmed to room temperature, diluted with diethyl ether (150 ml) and treated with 10% NH4OH solution (90 ml) for 5 minutes. The two phases are separated and the organic phase is washed with water followed by brine, dried over MgSO4 and concentrated to dryness. The oil is purified by flash silica chromatography (hexane) to give napthyltrimethyl stannane (2.69 g, 95.6%).
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=[O:36]>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=1)[OH:36]
Reactant: O=Cc1ccccn1
Reactant: CN(C)CCc1sc2ccccc2c1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CN(C)CCc1sc2ccccc2c1C(O)c1ccccn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 82.4 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (800 mg, 2.8 mmol) in anhydrous toluene (30 mL), TMEDA (420 uL, 2.8 mmol) was added followed by nBuLi (2.1 mL, 2.6 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and pyridine-2-carbaldehyde (800 uL, 8.4 mmol) was added. The mixture was stirred for 6 hrs during which the temperature reached 0° C., quenched with sat NH4Cl/NaHCO3 and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated and purified by silical gel column chromatography (gradient of DCM/MeOH=98/2 up to 94/6) to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-pyridin-2-yl-methanol (Compound 13-1) (721 mg) in 82% yield. MH+=313.0, tR=2.49 min (Method 2).
Reaction SMILES: [C:1]1([C@H:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>O>[N+:18]([C:4]1[CH:5]=[CH:6][C:1]([C@H:7]([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])=[CH:2][CH:3]=1)([O-:20])=[O:19]
Reactant: C[C@H](CC(=O)O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: C[C@H](CC(=O)O)c1ccc([N+](=O)[O-])cc1

Procedure:
(R)-3-phenylbutanoic acid (10.0 g) was added to concentrated sulphuric acid (40 mL) at −5° C. under nitrogen. The resulting thick gel-like mixture was stirred vigorously and fuming nitric acid (2.8 mL) was added slowly over 20 minutes. The reaction mixture was poured onto a mixture of ice and water (500 mL) and the resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (10.1 g) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][O:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[NH2:16][C:17]([NH2:19])=[S:18].[O-]CC.[Na+]>C(O)C>[CH:8]1([O:7][CH2:6][C:5]2[NH:19][C:17](=[S:18])[NH:16][C:3](=[O:2])[CH:4]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COC(=O)CC(=O)COC1CCCCC1
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1cc(COC2CCCCC2)[nH]c(=S)[nH]1
Reaction time: 16 h
Yield: 84.7 %

Procedure:
4-Cyclohexyloxy-3-oxo-butyric acid methyl ester (8.0 g) was added to a mixture of thiourea (34.7 g), sodium ethoxide (180 mL of 3 M ethanol solution) and ethanol (70 mL). The reaction was heated at reflux under nitrogen for 16 h. The ethanol was removed under vacuum. Residue was dissolved in water (400 mL) and the solution was cooled in an ice-bath. The solution was acidified with conc. hydrochloric acid to pH˜1 and stood at rt for 16 h. The solid that formed was collected by filtration to afford 6-cyclohexyloxymethyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (7.6 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH2:18])[CH3:17]>C(O)CCC>[CH2:16]([NH:18][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH3:17]
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Reactant: CCN
Solvent: CCCCO
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
7-Chloro-6-nitro-4(3H)-quinazolinone (20.0 g, 88.7 mmol) was suspended in n-butanol (150 ml), 70% aqueous ethylamine solution (120 ml) was added thereto, and the mixture was stirred for 15 minutes to give a clear solution which was then heated for 9 hours in a sealed tube in an oil bath (oil bath temperature set at 100° C. ). After the reaction was completed, the reaction mixture was left and cooled to precipitate yellow solids (first crystal) which were then filtered off. The first crystal was washed with methanol and ether and dried to give the desired title compound (8.27 g, 40%). The filtrate obtained at the time of acquisition of the first crystal was concentrated to precipitate crystal which was then filtered off and subjected to the same procedures as above to give second crystal as the desired title compound (5.84 g, 24%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([C@@H:28]2[CH2:30][C@H:29]2[C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31]([C@@H:29]3[CH2:30][C@H:28]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:32])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc1c23
Yield: 28 %

Procedure:
Preparation of example 61 from the title compound of Example 7 (198 mg, 0.72 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (175 mg, 1.08 mmol; as described by. A. Thurkauf, et al., J. Med. Chem. 43, 3923-3932, (2000)), triethylamine (0.401 mL, 2.88 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (411 mg, 1.08 mmol) in N,N-dimethylformamide (10.0 mL) was carried out analogously to Example 11. Silica gel chromatography (3% methanol in CH2Cl2), also in an analogous manner, followed by collection on a frit and subsequent washing with diethyl ether afforded the title compound (86 mg, 0.20 mmol) as a yellow powder in 28% yield.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>C(#N)C>[F:33][CH:34]1[CH2:39][CH2:38][N:37]([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[CH:4][CH:3]=2)[CH2:36][CH2:35]1
Reactant: FC1CCNCC1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)nc3)cc2)CCN1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(N4CCC(F)CC4)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 103.1 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-bromo-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D108) (0.050 g, 0.0993 mmol), 4-fluoropiperidine (0.055 g, 0.397 mmol) and triethylamine (0.069 mL, 0.497 mmol) in acetonitrile (4 mL) was heated at 85° C. overnight then in a microwave at 140° C. for 10 h. Further portions of 4-fluoropiperidine (5 eq.) and triethylamine (5 eq.) were added and the reaction heated at 170° C. for 2 h. The reaction mixture was concentrated and the residue dissolved in DCM/water. The aqueous layer was further extracted with DCM (×3) and the combined organics were dried (Na2SO4) and concentrated to give the title compound as a yellow oil (0.0538 g). MS (ES): MH+ 526.2.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:48][CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[CH2:21][CH2:22][CH:23]([F:47])[CH2:24][NH:25][C:26](=[O:46])[C@H:27]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:28][C:29]([O:31][CH3:32])=[O:30])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N+:63]([C:66]1[CH:71]=[CH:70][C:69]([S:72](Cl)(=[O:74])=[O:73])=[CH:68][CH:67]=1)([O-:65])=[O:64]>ClCCl>[Si:1]([O:18][CH2:19][C@@H:20]([N:48]([CH2:49][CH2:50][CH:51]([CH3:53])[CH3:52])[S:72]([C:69]1[CH:68]=[CH:67][C:66]([N+:63]([O-:65])=[O:64])=[CH:71][CH:70]=1)(=[O:73])=[O:74])[CH2:21][CH2:22][CH:23]([F:47])[CH2:24][NH:25][C:26](=[O:46])[C@H:27]([CH:33]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:28][C:29]([O:31][CH3:32])=[O:30])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NCCC(C)C)C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)NCC(F)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a stirred solution of the material from Step 12 (85 mg, 0.12 mmol) in dichloromethane (1.1 mL) were added N,N-diisopropylethylamine (30 μL, 0.172 mmol) and 4-nitrobenzenesulfonyl chloride (28 mg, 0.126 mmol). The reaction mixture was stirred at room temperature overnight. Additional N,N-diisopropylethylamine (30 μL, 0.172 mmol) and 4-nitrobenzenesulfonyl chloride (6 mg, 0.03 mmol) were added, stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel using EtOAc-hexanes to afford 85 mg of the title compound. LCMS (M+1)=947
Reaction SMILES: [Cl:1]([O-:3])=[O:2].[Na+].C(O)(=O)C(C)O.[C:11]([OH:23])(=[O:22])[CH2:12][C:13]([CH2:18][C:19]([OH:21])=[O:20])([C:15]([OH:17])=[O:16])[OH:14]>>[C:11]([OH:23])(=[O:22])[CH2:12][C:13]([CH2:18][C:19]([OH:21])=[O:20])([C:15]([OH:17])=[O:16])[OH:14].[Cl:1]([OH:3])=[O:2]
Reactant: [O-][Cl+][O-]
Agent: CC(O)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Product: [O-][Cl+]O

Procedure:
In practice, the reactants and reactions are produced by mixing bulk quantities of water, sodium chlorite and lactic acid to form an aqueous solution. In practice, about 1 part of lactic acid at a concentration of about 88% by volume, which is a food grade of lactic acid, is mixed with about 51 parts water and then mixed thoroughly by stirring. About three parts of sodium chlorite at a concentration of about 25-26% by volume is then added to this solution and again mixed. In practice, the water could vary from about 49-53 parts, the lactic acid could vary from about 0.8-1.2 parts and the sodium chlorite could vary from about 2.5-3.5 parts. Variations in the proportions or ratios of reactants in the ranges specified above results in variations in the concentrations of the end products of the reactions, e.g., the concentration of chlorine dioxide produced by these reactions. The 26% by volume of sodium chlorite and 88% by volume of lactic acid are commonly commercially available bulk quantities of these compounds and are generally provided to industry commercially in either drum lots or bulk quantities, for example, tank cars or tank trucks. Furthermore, note in the above reaction Number 1. that citric acid, HOC(CH2COOH)2COOH, at a concentration of about 55% by volume may be substituted for the lactic acid to produce a salt of citric acid and chlorous acid in an aqueous solution by using slightly different mixing ratios.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12])=O)C.CC(C[AlH]CC(C)C)C.O>C1(C)C=CC=CC=1>[OH:3][CH2:4][C:6]1[S:10][CH:9]=[N:8][C:7]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1scnc1C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1ncsc1CO
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 5.9 g (30 mmol) of 4-isopropyl-thiazole-5-carboxylic acid ethyl ester (J. Chem. Soc., Perkin Trans. 1, 1982:159-164) in toluene (100 mL) was cooled in an ice bath under nitrogen and treated dropwise with DIBAL (150 mL of 1.0 M; 150 mmol). The mixture was stirred at low temperature for 45 minutes and then allowed to warm to room temperature overnight. H2O was added cautiously, and the mixture was extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated. The crude 5-(hydroxymethyl)-4-isopropyl-thiazole thus obtained was used as is in the next step.