Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[N:26]3[N:27]=[C:28]([NH2:30])[N:29]=[C:25]3[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.NC1C=CC=C(Br)N=1>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[N:26]3[N:27]=[C:28]([NH:30][CH:10]4[CH2:11][CH2:12][N:7]([C:5]5[S:4][N:3]=[C:2]([CH3:1])[N:6]=5)[CH2:8][CH2:9]4)[N:29]=[C:25]3[CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: Nc1nc2n(n1)C(c1ccc(F)cc1)CCC2
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Agent: Nc1cccc(Br)n1
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)C(c3ccc(F)cc3)CCC4)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 5-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine. The latter compound can be prepared in analogy to example 1 steps d-g) starting from 2-amino-6-bromo-pyridine. The title compound was obtained as a white solid (yield=30%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:15][C@@:14]2([CH2:16][O:17][CH3:18])[CH2:13][NH:12][CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:19](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@:9]23[CH2:15][C@@:14]2([CH2:16][O:17][CH3:18])[CH2:13][N:12]([CH3:19])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)O
Reactant: COC[C@]12CNCC[C@@]1(c1ccc(Cl)c(Cl)c1)C2
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC[C@]12CN(C)CC[C@@]1(c1ccc(Cl)c(Cl)c1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1S,6R)-6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane (E2a, 25 mg) was dissolved in methanol (1 mL); acetic acid (0.015 mL) was added followed by sodium triacetoxyborohydride (27.8 mg) and formaldehyde 37% in water (0.06 mL). The reaction mixture was stirred at room temperature overnight. Volatiles were then evaporated and the residue partitioned between DCM (20 mL) and aqueous sat NaHCO3 (20 mL) solution, dried and concentrated. Purification by chromatography (NH column) eluting with a gradient 0-100% ethyl acetate-cyclohexane afforded the title compound (16 mg).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=O)C1C=CC=CC=1.CO.[ClH:46]>[C].[Pd].C1COCC1>[ClH:46].[CH3:28][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:19]1[C:17]([NH:16][C@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:18]
Reactant: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c(C(=O)N[C@@H](CCCN)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (3.0 g), methanol (50 ml), and THF (50 ml) were added 1 M hydrochloric acid (5.1 ml) and palladium-carbon (5.4 g) under ice-cooling, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. The insolubles of the reaction mixture were separated by filtration through Celite and the filtrate was concentrated under reduced pressure to obtain tert-butyl (1R,2S)-2-({N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate hydrochloride (2.6 g).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:15]=[N:16][OH:17]>CCCCCC.O1CCCC1.ClCCl>[CH2:3]([O:17][N:16]=[CH:15][C:14]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:12]([Cl:11])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: ClCCl
Product: Clc1ccc(C=NOCc2ccccc2)cc1Cl
Temperature: 22 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Sodium hydride (1.05 g of 60% suspension in mineral oil, 0.63 g, 26.3 mmol) was washed with hexane, suspended in tetrahydrofuran (10 ml) and then treated with benzyl bromide (2.7 ml, 22.8 mmol) A solution of the above oxime in tetrahydrofuran (10 ml) was then added dropwise and the resulting mixture was stirred at 22° C. for 18 h. The reaction mixture was then diluted with dichloromethane, washed with water, brine and dried. Evaporation of the solvent and chromatography of the residue on silica gel (elution hexane-toluene, 8:2 to 1:1) gave 4.30 g (67% yield) of the title oxime ether as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.12 (2H, s, OCH2), 7.3-7.44 (7H, m, aromatics), 7.68 (1H, d, aromatic), 8.04 (1H, s, CH).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:20]=2)=[CH:12][CH:11]=1.C(O)(=O)C>ClCCl>[Br:8][C:18]1[O:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:20][C:19]=1[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Fc1ccc(-c2nc(-c3ncccn3)co2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(-c2nc(-c3ncccn3)c(Br)o2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NBS (2.03 g, 11.4 mmol) and 2-[2-(4-fluorophenyl)-1,3-oxazol-4-yl]pyrimidine (1.4) (2.5 g, 10.36 mmol) in a solvent mixture of 1:1 acetic acid and dichloromethane were stirred at room temperature for 3 hr. Then the solvents were removed in vacuo, and the resulting residue was dissolved in EtOAc. The solution was washed with aqueous Na2S2O3 and brine, and dried over MgSO4. The drying agent was filtered off and the filtrate was concentrated to give the title compound. LC-MS m/z 321.96 [M+1]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([CH2:36][CH2:37][NH:38][C:39]([CH3:51])([CH3:50])[CH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=1)=O)(C)(C)C.[C:52](OC(CCNC(C)(C)CC1C=CC(C(CCNC2C=C(OC)C=CC=2C2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:45][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][C:39]([N:38]([CH2:37][CH3:36])[CH3:52])([CH3:50])[CH3:51])=[CH:49][CH:48]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(CC(C)(C)NCCC(=O)OC(C)(C)C)cc2)c1
Reactant: CC(C)(Cc1ccc(C(=O)O)cc1)NCCC(=O)OC(C)(C)C
Product: CCN(Cc1ccc(CC(C)(C)N(C)CC)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 37.7 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-[2-(tert-butoxycarbonylethylamino)-2-methylpropyl]benzoic acid (125 mg) according to an analogous synthetic method to Preparation Example 86, pivalic acid 6-{2-{{4-[2-(tert-butoxycarbonylethylamino)-2-methylpropyl]benzoyl}ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (69 mg) was used according to an analogous synthetic method to Example 337 to provide the title compound (19 mg).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].[CH3:22][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:22][O:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[N:11]1[C:12](=[O:21])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccccc2C[C@H]1O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CO[C@@H]1Cc2ccccc2[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 46 %

Procedure:
To a solution of 2-[(1R,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (0.860 g, 0.00308 mol) in THF (30 mL) at 0° C. under an atmosphere of nitrogen was added a 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 20 minutes, followed by the addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir and warm to rt over 18 h. The reaction was monitored by 1H NMR. The reaction mixture was then re-cooled to 0° C. To the reaction mixture was added 1.0 M solution of lithium hexamethyldisilazide in THF (3.39 mL, 0.00339 mol). The reaction mixture was stirred for 15 minutes, followed by addition of methyl iodide (0.575 mL, 0.00924 mol). The cold bath was removed, and the reaction mixture was allowed to stir at rt for 22 h. 1H NMR indicated 80:20 product/starting material. The reaction was quenched with aqueous 1N HCl solution and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic phase was washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated. The oil was purified by silica gel chromatography, eluting with a gradient of hexanes to 10% EtOAc in hexanes) to obtain product (4.18 g, 46%). LC/MS: Rt=1.90 min, ES+ 294 (AA standard).
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N(C([O:25][CH2:26][CH3:27])=O)=NC(OCC)=O>C(OCC)C.C1C=CC=CC=1>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][S:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:26]([C:27]1[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=1)=[O:25])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: O=C(c1ccccc1)c1ccccc1S
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccccc1SSc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50.7 %

Procedure:
To a solution of 2-mercaptobenzophenone (2.3 g, 7.4 mmol) in diethyl ether (10 mL) was added dropwise diethyl azodicarboxylate (0.65 g, 3.7 mmol). The solution was stirred for 5 minutes at room temperature, then diluted with benzene (40 mL) and refluxed for 16 hours. The solution was cooled and concentrated in vacuo leaving a yellow liquid. The crude product was purified using silica gel chromatography (75% hexane/25% ethyl acetate) to give the title compound as a yellow foam (0.8 g, 50%);
Reaction SMILES: CCN=C=NC[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].C(N(CC)CC)C.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:24][CH:23]=1.C(O)(C(F)(F)F)=[O:40]>C(Cl)Cl>[CH3:10][N:9]([CH3:11])[CH2:8][C:7]([NH:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29](=[O:38])[N:30]([CH3:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][CH:27]=1)=[O:40]
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CC(=O)NCCc1ccc(OC(=O)N(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
A solution of N,N-dimethylglycine, HCl (0.3 mmol), EDAC (0.36 mmol) and triethylamine (1.0 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 66% yield as an oil.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([CH:16]([CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15])C1C=CC=CC=1.[OH:34]O.O.[OH-].[Li+]>O1CCCC1.O>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH:16]([CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:14]([OH:15])=[O:34])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(CCCC1CCCCC1)C(=O)O
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of tert-butyl 3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-cyclohexylhexanoate (64.0 g, 139.9 mmol) in tetrahydrofuran:water (3:1, 800 ml) was cooled to 5° C. then treated sequentially with hydrogen peroxide (30% w/v water, 87 ml, 769 mmol) then lithium hydroxide hydrate (10.0 g, 238 mmol). The reaction was stirred for 1 hour then quenched by dropwise addition of an aqueous solution of sodium thiosulphate (500 ml) keeping the temperature below 20° C. The mixture was extracted with ethyl acetate (discarded) and the aqueous phase was acidifed to pH 2 with solid citric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (2:1) gradually changing to hexane:ethyl acetate (1:1) to afford the title compound (40.7 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][CH:6]([CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:10])[CH2:7][OH:8].CS(Cl)(=O)=O.C(N([CH2:33][CH3:34])CC)C.[I-].[K+].C(O[CH2:41][CH3:42])(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][CH:6]([CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:16])[CH3:17])([CH3:14])[CH3:13])[CH3:10])[CH2:7][O:8][C:34]1[CH:33]=[CH:42][C:41]2[C:3](=[CH:2][CH:21]=[CH:20][CH:19]=2)[CH:4]=1
Reactant: CCOC(C)=O
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(CO)Cc1ccc(Cl)c(Cl)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(COc1ccc2ccccc2c1)Cc1ccc(Cl)c(Cl)c1
Yield: 29 %

Procedure:
200 mg of the alcohol compound thus obtained was dissolved in 5 ml of ethyl acetate, and 55 μl of methanesulfonyl chloride and 120 μl of triethylamine were added thereto with stirring under cooling with ice, and the mixture was stirred at the same temperature for 30 minutes. Formed precipitate was separated by filtration, and the filtrate was evaporated to dryness under reduced pressure. Then, the residue was dissolved in 5 ml of dimethylformamide. Separately, 87 mg of 2-naphthol was dissolved in 5 ml of dimethylformamide, and 24 mg of 60% oily sodium hydride was added. The mixture was stirred at room temperature for 30 minutes. To this solution, the dimethylformamide solution of the mesylated compound obtained above, was added under stirring. Further, 91 mg of potassium iodide was added thereto. Then, the mixture was stirred at room temperature for 3 days. The reaction solution was poured into water and extracted by an addition of ethyl ether. Then, the ether extract solution was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 77 mg (yield: 29%) of (2RS, 3RS)-2-(3,4-dichlorobenzyl)-3-(tert-butyldimethylsilyloxy)-1-(2-naphthoxy)butane.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[NH2:10][C:11]1[N:16]=[C:15]([NH2:17])[C:14]([CH:18]=O)=[CH:13][N:12]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:9])=[N:17][C:15]2[N:16]=[C:11]([NH2:10])[N:12]=[CH:13][C:14]=2[CH:18]=1
Reactant: N#CCc1ccccn1
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3ccccn3)c(N)nc2n1

Procedure:
The procedure of Example 1 was followed to react 0.84 mL of 2-pyridylacetonitrile and 1.0 g of 2,4-diamino-5-pyrimidinecarboxaldehyde to afford the title compound, mp 312°-321° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:4]([OH:16])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8].Cl.N[C@@H](CCCC)[C@H](O)CNS(C1C=CC=CN=1)(=O)=O.C(N(CC)C(C)C)(C)C.[C:50](=O)([O:73]C1C=CC([N+]([O-])=O)=CC=1)[O:51][C@H:52]([CH2:57][N:58]1[CH:62]=[CH:61][C:60]([C:63]2[CH:68]=[CH:67][C:66]([C:69]([F:72])([F:71])[F:70])=[CH:65][CH:64]=2)=[N:59]1)[C:53]([CH3:56])([CH3:55])[CH3:54]>CN(C)C=O.C(OCC)(=O)C>[OH:16][C@H:4]([C@@H:3]([NH:2][C:50](=[O:73])[O:51][C@H:52]([CH2:57][N:58]1[CH:62]=[CH:61][C:60]([C:63]2[CH:64]=[CH:65][C:66]([C:69]([F:70])([F:71])[F:72])=[CH:67][CH:68]=2)=[N:59]1)[C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8]
Reactant: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Reactant: CC(C)(C)[C@@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCCC[C@H](N)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
To a solution of 90 mg (0.21 mmol) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride and 83 mg (0.63 mmol) of N,N-diisopropylethylamine in 2 mL N,N-dimethylformamide was added 102 mg (0.21 mmol) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl 4-nitrophenyl carbonate. The reaction mixture was stirred at room temperature for 48 h. It was diluted with ethyl acetate, washed with one portion of 1M sodium hydroxide and with 1 portion of brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate:hexanes (3:1) to afford 90 mg (68%) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 8.70 (d, J=4 Hz, 1H), 8.11–7.45 (m, 10H), 6.76 (s, 1H), 6.54 (d, J=9 Hz, 1H), 4.90–4.76 (m, 2H), 4.46 (d, J=13 Hz, 1H), 4.16 (m, 1H), 3.05 (m, 1H), 1.27 (m, 1H), 1.05–0.86 (m, 14H), 0.68 (m, 3H); ES-LCMS m/z 648 (M+Na).
Reaction SMILES: C(OC(N1C2C(=CC=C([Br:15])C=2)C(O)=N1)=O)C.[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[C:26](Br)[CH:27]=[CH:28][CH:29]=2)[C:24]([O:32][CH3:33])=[N:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([Br:15])=[CH:28][CH:29]=2)[C:24]([O:32][CH3:33])=[N:23]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)n1nc(O)c2ccc(Br)cc21
Reactant: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Product: CCOC(=O)n1nc(OC)c2cc(Br)ccc21

Procedure:
5-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CCXXXVI was prepared from 6-bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester using the procedure described for preparation of 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV (Example 37).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C@H:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][C@@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:26]([C@H:17]1[CH2:18][CH2:19][C@@H:20]([C:23]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:25])[CH2:21][CH2:22]1)=[O:28])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)[C@H]1CC[C@@H](C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)CC1

Procedure:
Using General Procedure A with 2.0 g (8.2 mmol) D-Proline benzyl ester hydrochloride and 700 mg (4.1 mmol) cis-cyclohexane-1,4-dicarboxylic acid afforded, after flash chromatography (EtOAc), 2.0 g (91%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100).
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:14][CH:11]1OC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:43]([OH:46])(=[O:45])[CH3:44].N1C=CC=CC=1.S(=O)(=O)(O)O>O>[C:43]([O:46][CH:11]1[O:14][C@@H:15]([CH2:26][O:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:10]1[O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)O
Reactant: COC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
59.40 g out of 62.69 g of the crude 2,3,5-tri-O-benzoyl-1-O-methyl-L-ribofuranose synthesized in (2) above was added to a 1-L flask. Thereafter, acetic anhydride (31.2 ml; 2.65 equivalents), acetic acid (26.7 ml; 3.73 equivalents), and pyridine (7.1 ml; 0.8 equivalents) were added to the flask. The obtained mixture was cooled to an ice-cooled temperature, and thereafter, concentrated sulfuric acid (13.5 ml; 2.03 equivalents) was slowly added dropwise thereto. After completion of the reaction for 30 minutes, cold water (200 ml) was slowly added dropwise to the reaction product, and crystals were then filtrated. The obtained solid was dried. Thus, 69.83 g of crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was obtained in the form of a light yellow solid. The obtained compound was analyzed by HPLC. As a result, the ratio of α-/β-anomers in the 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was 4/96, and the reaction yield of the β-anomer from the total 3 steps was 84%. 69.83 g of the crude 1-O-acetyl-2,3,5-tri-O-benzoyl-L-ribofuranose was suspended in isopropyl alcohol (92 ml), and the suspension was then heated to reflux for 1 hour. Thereafter, the reaction solution, in which the aforementioned compound had been completely dissolved, was cooled to an ice-cooled temperature, and it was then stirred for 30 minutes. Thereafter, the resultant mixture was filtrated, and the obtained crystals were then dried under reduced pressure. Thus, 1-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose was obtained from L-ribofuranose in the form of white crystals with a purity of 99% or more at a total yield of 75%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[BH-](O[C:25](=[O:27])[CH3:26])OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:7][C:6]2[O:27][C:25]3[C:26](=[N:9][CH:4]=[CH:3][CH:8]=3)[CH:5]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccccc1N1CCN(Cc2cc3ncccc3o2)CC1

Procedure:
The product from Example 35B, 1-(2-methoxyphenyl)piperazine, and sodium triacetoxyborohydride were processed as described in Example 35C to provide the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.85 (br, 4H), 3.19 (br, 4H), 3.85 (s, 3H), 3.88 (s, 2H), 6.93 (m, 5H), 7.20 (dd, 4.75, 8.14 Hz, 1H), 7.74 (m, J=1.02, 7.12 Hz, 1H), 8.54 (br, 1H); MS (DCI/NH3) m/z 324.2 (M+H)+; Anal Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99. Found: C, 69.72; H, 6.45; N, 12.81.