Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][CH2:12][N:10]2[N:11]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](Br)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:25][C:21]2[CH:20]=[C:19]3[C:24]([C:15]([C:8]4[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)=[N:11][N:10]5[CH2:12][CH2:13][CH2:14][C:9]=45)=[CH:16][CH:17]=[N:18]3)=[CH:23][CH:22]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)CC1
Temperature: 80 °C

Procedure:
To a suspension of 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (0.27 g, 0.84 mmol) in N,N-dimethylformamide (15 mL) is added 4-bromo-piperidine-1-carboxylic acid tert-butyl ester (0.29 mL, 2.28 mmol) and cesium carbonate (1.5 g, 4.57 mmol. The mixture is heated at 80° C. for 48 h and concentrated in vacuo. The residue is taken up in dichloromethane, washed with water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (SiO2, 7% methanol in dichloromethane) yields the title compound, 262 mg (61%,) as a yellow oil.
Reaction SMILES: [Cl-:1].[CH2:2]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][NH+:10]([CH3:12])[CH3:11])[CH3:3].Cl.[CH2:15](O)[CH2:16]CC>>[Cl-:1].[CH2:2]([O:4][C:5](=[O:13])[NH:6][CH2:7][CH2:8][CH2:9][NH+:10]([CH3:11])[CH3:12])[CH2:3][CH2:15][CH3:16]
Reactant: CCCCO
Reactant: CCOC(=O)NCCC[NH+](C)C
Agent: Cl
Agent: [Cl-]
Product: CCCCOC(=O)NCCC[NH+](C)C

Procedure:
21.0 g (0.1 mole) of N-(3-dimethylammoniopropyl)-carbamic acid ethyl ester chloride are suspended in 100 ml of n-butanol. Dry HCl gas is introduced into the suspension for a short time and the mixture is heated for 6 hours at 100° to 115° C while stirring, the hydrochloride going into solution and some ml of liquid distilling off. Then concentrate and drag the residue in vacuum. One obtains 18.0 g of nD20 = 1.4750.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2
Reactant: C1COCCN1
Product: O=C(c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2)N1CCOCC1

Procedure:
This compound was prepared from 2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and morpholine according to Example 269f; waxy solid, MS: m/e=526 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:17][C:15]1[CH:14]=[CH:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][S:10][C:11]=2[CH:16]=1
Reactant: Oc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Reactant: BrCCCCBr
Product: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1

Procedure:
In analogy to example 2.1, 3-(4-chloro-phenyl)-benzo[d]isothiazol-6-ol and 1,4-dibromobutane were converted to yield 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole as white solid, mp: 68-69° C., MS: 395 (M, 1Br, 1 Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][C:5]#[N:6].O1CCCC1.[CH2:17](Br)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O>[CH2:17]([CH:4]([C:5]#[N:6])[C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: N#CCc1ccc(Cl)cc1Cl
Reactant: CCCCCCCCBr
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCC(C#N)c1ccc(Cl)cc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (0.13 moles as a 50% dispersion in mineral oil) is washed with 100 ml. of dry n-hexane to remove the mineral oil, then blanketed with dry nitrogen and suspended in 250 ml. of freshly distilled tetrahydrofuran. To this sodium hydride suspension is added dropwise at room temperature, a solution of 2,4-dichlorobenzyl cyanide (25 g., 0.13 mole) dissolved in 100 ml. of tetrahydrofuran. When the addition is completed the temperature is maintained at 30° C. for an additional 0.5 hours. A solution of n-octylbromide (27 g., 0.14 mole) is then added dropwise and the resultant reaction mixture is stirred at 40° C. overnight under nitrogen. The reaction mixture is poured into 1 liter of water and extracted with (3×200 ml.) of ether. The combined ether extracts are washed, with water, dilute hydrochloric acid, saturated sodium, bicarbonate solution saturated sodium chloride solution, and dried over magnesium sulfate. The solvent is evaporated to give 39.8 g. (100%) of product.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)c(C)c1

Procedure:
115 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(2,4-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6]Br.[NH2:8][C@@H:9]([CH3:12])[CH2:10][OH:11]>ClCCl>[O:4]1[CH2:5][CH2:6][N:8]([C@@H:9]([CH3:12])[CH2:10][OH:11])[CH2:2][CH2:3]1
Reactant: BrCCOCCBr
Reactant: C[C@H](N)CO
Solvent: ClCCl
Product: C[C@@H](CO)N1CCOCC1
Reaction time: 0.32 h
Yield: 87.5 %

Procedure:
Bis(2-bromoethyl)ether (2.3 g, 10 mmol) was added to (5)-2-aminopropan-1-ol (3.8 g, 50 mmol) at room temperature with vigorous stirring. The reaction slowly exothermed and the internal temperature peaked at 42° C. after 19 min. After 24 h, the reaction was diluted with dichloromethane (10 mL) and quenched with saturated aqueous potassium carbonate solution (10 mL). Water (˜2.5 mL) was added to the heterogeneous mixture until the solids dissolved. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×10 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude material was purified by silica gel chromatography (10:7; ethyl acetate:hexanes→10:7:2:1; ethyl acetate:hexanes:methanol:triethylamine) to give 1.27 g of (S)-2-morpholinopropan-1-ol. 1H NMR (DMSO-d6): δ 4.29 (dd, 1H), 3.54 (t, 4H), 3.45 (ddd, 1H), 3.25 (ddd, 1H), 2.54-2.40 (m, 5H), 0.92 (d, 3H); LCMS: 146.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH2:6].[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23](O)=[O:24])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1>>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][C:23](=[O:24])[CH:21]([CH3:22])[NH:20][C:15]1[CH:16]=[C:17]([F:19])[CH:18]=[C:13]([F:12])[CH:14]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCC[C@H](N)C(=O)OC
Reactant: CC(Nc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: CCCC[C@H](NC(=O)C(C)Nc1cc(F)cc(F)c1)C(=O)OC

Procedure:
Following General Procedure E and using L-norleucine methyl ester hydrochloride (Sigma) and N-(3,5-difluorophenyl)-D,L-alanine, the title compound was prepared as a solid (mp=93-95° C.). The reaction was monitored by tlc (Rf=0.6 in 3% methanol/methylene chloride) and purification of this compound was by flash chromatography with 3% methanol/methylene chloride.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:13]([OH:29])[C:14]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])=[O:15])=O)C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[NH2:11][CH:12]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH:13]([OH:29])[C:14]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][CH2:27][CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])=[O:15]
Reactant: C[C@H](NC(=O)C(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: C[C@H](NC(=O)C(O)C(N)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 89.4 %

Procedure:
Crude (S,S)-1-[N-[3-[(benzyloxycarbonyl)amino]-2-hydroxy-1-oxo-4-phenylbutyl]-L-alanyl]-L-proline (about 2 mmol) is dissolved in 50 ml of methanol and 25 ml of water. After sweeping the system with argon 0.5 g of 10% palladium on charcoal is added. While stirring, a slow stream of hydrogen is passed over the surface for eighteen hours. The catalyst is removed by filtration through diatomaceous earth and the pad is washed with methanol. The filtrate is taken to dryness in vacuo and methanol is added four times and removed in vacuo leaving 0.65 g of a glass. This material is combined with that from another run. Most of this material is dissolved in 5 ml water and is applied to a column packed with 12 ml AG50WX2 (H+) resin. The column is eluted with water until the eluate is no longer strongly acidic and then is eluted with pH 6.5 buffer. Fractions positive to ninhydrin are pooled. It appears that some of the product has precipitated on the column so when fractions give only a very weak test with ninhydrin the remaining product is eluted with 2 N NH4OH. The two pools are worked up separately by taking to dryness in vacuo and adding water and again taking to dryness. Electrophoresis on the two materials are identical; -5.3 cm (pH 1.9 buffer, 2000 V, 30 min., detected ninhydrin and I2). The two pools are combined, triturated with water, the solid harvested by filtration, washed with more water and then with methanol. Drying in vacuo over P2O5 at 75° C. gives the analytical sample (412 mg), [α]D =-120° (c=0.64, acetic acid).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34](O)=[O:35])[C:28]=2[CH:27]=[CH:26][N:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:29]3[C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:33]=4[CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2cnccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4cnccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with isoquinoline-5-carboxylic acid. LC-MS (basic): tR=0.74 min; [M+H]+=488.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][CH2:27][O:28][CH3:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([C:8]2[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][N:11]([CH2:26][CH2:27][O:28][CH3:29])[N:12]=2)[CH:7]=1
Reactant: COCCBr
Reactant: CCOC(=O)c1cn[nH]c1-c1cc(Cl)ccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCOC)nc1-c1cc(Cl)ccc1C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A solution of ethyl 5-(5-chloro-2-methylphenyl)-1H-pyrazole-4-carboxylate (0.2286 g, 0.8636 mmol), cesium carbonate (359.1 mg, 1.102 mmol, 1.276 equiv) and 1-bromo-2-methoxyethane in N,N-dimethylformamide (6 mL) was heated at 50° C. After 2.5 hours, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered, and concentrated to yield 257.7 mg (92%) of ethyl 3-(5-chloro-2-methylphenyl)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate, which was carried forward without purification. LCMS (ESI) m+H=323.2.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16].CC(C)([O-])C.[K+].O>CC(N(C)C)=O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[CH3:26])[N:19]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:29][CH:28]=2)[C:18]1=[O:34])[CH3:16]
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C)c21
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C)c21
Temperature: 95 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
120s′) A solution of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (78.4 g, 371.33 mmol) in DMA (420 mL) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100.0 g, 371.33 mmol) and potassium tert-butoxide (51.5 g) in DMA (370 mL) at room temperature. The mixture was stirred at 90-100° C. for 1 h. Water (780 mL) was added at 90-100° C. The precipitate was collected at room temperature and dried under reduced pressure to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (127.7 g) as crystals. The obtained crystals (125.0 g) were dissolved in DMSO (1375 mL) at 90-95° C. To the solution was slowly added EtOH (1250 mL) at 80-95° C., and then the mixture was allowed to cool to room temperature. The solid was collected by filtration and washed with EtOH (625 mL) to give 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103.9 g) as crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([CH2:12][OH:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>ClCCl>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:11][C@H:10]([CH:12]=[O:13])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](CO)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](C=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
To a solution of trans-(3-hydroxymethyl-cyclobutyl)-carbamic acid tert-butyl ester (Compound 4a) (0.2 g; 1.0 mmol) in anhydrous dichloromethane (8.0 mL) at 0° C. was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-one (0.84 g; 2.0 mmol). The reaction was allowed to stir at room temperature under nitrogen for 3 h, before partitioning the reaction mixture between dichloromethane and brine. The organic layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash column chromatography, eluting with 30% ethyl acetate in hexanes, to yield Compound 4b as a foam (0.2 g; 88% yield). 1H NMR (400 MHz, CDCl3): δ 9.82 (1H, d), 4.77 (1H, br s), 4.16-4.11 (1H, br s), 3.04-3.03 (1H, m), 2.69-2.64 (2H, m), 2.21-2.13 (2H, m), 1.44 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][C@@H:12]2[C@@H:17]3[O:18][C@@H:14]([CH2:15][CH2:16]3)[C@@H:13]2[C:19]([NH2:21])=[O:20])[C:5]([Cl:22])=[CH:4][N:3]=1>[Ni]>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][CH:12]2[CH:17]3[O:18][CH:14]([CH2:15][CH2:16]3)[CH:13]2[C:19]([NH2:21])=[O:20])[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2[N+](=O)[O-])[C@H]2CC[C@@H]1O2
Agent: [Ni]
Product: NC(=O)C1C2CCC(O2)C1Nc1c(Cl)cnc(N)c1N
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To a suspension of Raney Nickel (70 mg) in MeOH (25 ml) (1S,2R,3S,4R)-3-(2-amino-5-chloro-3-nitropyridin-4-ylamino)-7-oxabicyclo[2.2.1]heptane-2-carboxamide (16) (150 mg, 0.458 mmol) was added and the reaction mixture was hydrogenated for 2 h at rt. The reaction mixture was filtered through a bed of celite and the bed was washed well with MeOH. The filtrate was concentrated to afford the product (131 mg, 96%) as a white solid. LCMS (254 nm): [M+H]+ 298.10 (99.9%)
Reaction SMILES: C(OC([N:8]1[CH2:38][CH2:37][C:11]2([O:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=3)[CH:12]2[CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH2:45](Br)[CH3:46].[ClH:48]>CN(C=O)C.C(OCC)C>[ClH:48].[F:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][CH:12]2[C:11]3([CH2:37][CH2:38][N:8]([CH2:45][CH3:46])[CH2:9][CH2:10]3)[O:15][C:14](=[O:16])[N:13]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:23]=2)=[CH:35][CH:34]=1
Reactant: CC(C)COc1ccc(CN2C(=O)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2Cc2ccc(F)cc2)cc1
Reactant: CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCN1CCC2(CC1)OC(=O)N(Cc1ccc(OCC(C)C)cc1)C2Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
69NLS77 (190 mg, 0.45 mmol) was N-BOC deprotected as described in the preparation of 69NLS79-II and dissolved in DMF (3 mL). Potassium carbonate (250 mg, 1.80 mmol) was added, followed by ethylbromide (50 μL, 0.45 mmol)) and the mixture stirred overnight at rt. Workup was carried out as for 69NLS79-II. The residue was purified by silica gel column chromatography, eluting with a stepwise gradient of 0-6% methanol in dichloromethane, followed by repurification of the compound by acidic ion-exchange SPE cartridge, to give 38-PH20 (77 mg, 38%) as a colourless oil. The compound was converted to its hydrochloride form by treatment with 2M HCl in diethylether as described above, giving the salt as a colorless powder.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:14][CH2:15]O>>[O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([O:9][CH2:14][CH3:15])=[O:8])[CH2:4][CH2:3]1
Reactant: CCO
Reactant: O=C1CC[C@H](C(=O)O)N1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-5-oxopyrrolidine-2-carboxylic acid (10 g, 69.84 mmol; available from Aldrich#422614) in EtOH (100 ml) cooled at −5° C., thionyl chloride (10 ml, 139.68 mmol) was added and the resulting mixture was stirred at RT for 3 hrs. Solvents were evaporated in vacuo and the resulting residue was taken up with EtOAc (350 ml), washed with water/TEA (40/12 ml), then with water (40 ml). Collected organics were dried over Na2SO4 and evaporated to afford a residue that was loaded on a SNAP-Si cartridge (50 g) and eluted with a mixture DCM/EtOAc from 90/10 to 50/50. Collected fractions after solvent evaporation afforded a first batch of title compound (D23) (6.4 g). The aqueous were saturated with NaCl and extracted with EtOAc (400 ml). The organic was washed with water (20 ml) dried over Na2SO4 and evaporated in vacuo to afford a second batch of title compound (D23) (3.7 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH2:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Reactant: NCC1CC1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)c(F)c1
Yield: 55.6 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylmethylamine (0.32 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-3-fluorobenzenesulfonamide (0.25 g, 55%) was provided after purification. HRMS: calcd for C10H11BrFNO2S−H+, 305.96051; found (ESI, [M−H]−), 305.9603. HPLC purity 100.0% at 210-370 nm, 10.5 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:6]2[N:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH:21]([CH3:23])[CH3:22]>ClCCl>[CH3:22][CH:21]([CH3:23])[C:20]([N:9]1[CH2:10][CH2:11][N:6]2[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:7]2[CH2:8]1)=[O:24]
Reactant: CC(C)C(=O)Cl
Reactant: O=[N+]([O-])c1cc2n(n1)CCNC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1CCn2nc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-nitro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine 124d (160 mg, 0.952 mmol) in dichloromethane (10 mL) was added triethylamine (197 mg, 1.90 mmol). After stirring at room temperature for 5 minutes, a solution of isobutyryl chloride (111.0 mg, 1.047 mmol) in dichloromethane (2 mL) was added and the mixture was stirred for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. It was then concentrated under reduced pressure to afford 148a as a white solid (220 mg, 97%), which was used in the next step without further purification. MS-ESI: [M+H]+ 239.0
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]3[C:24](=[O:32])[NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:33][O:34][C:35]1[CH:56]=[CH:55][C:38]([C:39](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[CH:37][CH:36]=1>N1C=CC=CC=1>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:22][C@H:21]([OH:23])[CH2:20][C@H:19]3[C:24](=[O:32])[NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][C:39]([C:38]3[CH:55]=[CH:56][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(NCCOCCO)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Product: COc1ccc(C(OCCOCCNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
(2S,4R)-4-Hydroxy-2-[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (Compound 72) (1.69 g, 3.83 mmol) and 4,4′-dimethoxytrityl chloride (2.47 g, 7.66 mmol) were dissolved in pyridine (5.0 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was purified by reverse-phase silica (0.1% ammonium acetate, H2O, CH3OH, gradient) to afford the title compound (Compound 73) (2.24 g, 79%) as a pale yellow amorphous.