Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:28][CH3:29])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:39][C:40]1[C:59]([F:60])=[CH:58][CH:57]=[CH:56][C:41]=1[CH2:42][NH:43][C:44](=[O:55])OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]([N:28]([CH3:29])[C:44]([NH:43][CH2:42][C:41]1[CH:56]=[CH:57][CH:58]=[C:59]([F:60])[C:40]=1[Cl:39])=[O:55])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a solution of (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(methylamino)pentanoyl)piperazine-1-carboxylate (16 g, 37.3 mmol) and DIEA (1.3 mL, 7.46 mmol) in THF (180 mL) was added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (12 g, 37.3 mmol). The reaction mixture was stirred at RT for 2 h and concentrated. The residue was purified on silica gel using a mixture of EtOAc and hexanes to give (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate (14.3 g, 62.4% for three steps). LRMS (M+H) m/z 615.3.
Reaction SMILES: [CH:1]1([SH:4])[CH2:3][CH2:2]1.C1(Br)CC1.[H-].[Na+].Br[C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CS(C)=O.CCOCC>[CH:1]1([S:4][C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1
Reactant: SC1CC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: BrC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(F)(F)SC1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
An ether solution of cyclopropyl mercaptan synthesized from cyclopropyl bromide (50.0 g, 413 mmol) in accordance with the process described in literature (J. Am. Chem. Soc., 114, 3492 (1992)) was added dropwise to a solution of 60% sodium hydride (5.4 g, 135 mmol) in dimethyl sulfoxide (100 ml) under cooling with ice, and the mixture was stirred at room temperature for 10 minutes. A solution of ethyl bromodifluoroacetate (27.4 g, 135 mmol) in dimethyl sulfoxide (200 ml) was added dropwise to this solution under cooling with ice, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water to conduct extraction with ether. The solvent was distilled out of the resultant extract under reduced pressure. The resultant residue was distilled under reduced pressure to obtain the intended product (12.3 g; yield: 46.0%) as a colorless oil.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]1([CH3:27])[CH3:26].C([O-])(O)=O.[Na+]>O1CCCC1.O>[CH2:5]([O:4][C:2]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]1([CH3:27])[CH3:26])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(C)(C)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C(C)(C)C1
Temperature: 35 °C
Reaction time: 20 h

Procedure:
Benzyl chloroformate (50% in toluene, 450 ml, 1.57 mol) was added to a stirred suspension of 4-amino-1-t-butyloxycarbonyl-3,3-dimethylpiperidine (365 g) as prepared above and NaHCO3 (150 g, 1.78 mol) in dry tetrahydrofuran (1.5 L). The reaction mixture was stirred for 20 hr at 35° C. The reaction mixture was diluted with 3.5 L water and was extracted with 2.0 L×2 ethyl acetate. Combined organic extract was washed with water, dried over Na2SO4 and concentrated to dryness. The residue was subjected to chromatography on a silica gel column to give 4-benzyloxycarbonylamino-1-t−butyloxycarbonyl-3,3-dimethylpiperidine in 63% (350 g) yield. m/z 363 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NCc1ccc(F)cc1
Reaction time: 1 h
Yield: 55.2 %

Procedure:
4-Fluorobenzylamine (11.4 g, 91 mmol) was dissolved in 910 mL of CH2Cl2. To this was added 910 mL of satd NaHCO3 followed by acetyl chloride (23.4 mL, 329 mmol) stir 1 h. The organic layer was separated, washed with satd NaCl, dried over Na2SO4, filtered and solvent removed to yield 8.4 grams of N-(4-fluoro-benzyl)-acetamide.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([CH2:9][OH:10])[N:6]=[CH:5]1)([CH3:3])[CH3:2].[CH3:11][C:12]([Si:15](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH3:13].O>ClC(Cl)C.CN(C1C=CN=CC=1)C>[Si:15]([O:10][CH2:9][C:7]1[N:6]=[CH:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=1)([C:12]([CH3:14])([CH3:13])[CH3:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)n1cnc(CO)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(C)n1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Reaction time: 17 h

Procedure:
This (1-isopropyl-1H-imidazol-4-yl)methanol was dissolved in dichloroethane (200 mL), and at room temperature TEA (10.9 mL), TBDPSCl (10.2 mL) and DMAP (0.320 g) were added, followed by stirring for 17 hours. The reaction solution was poured into water, and extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=20%→100%) using silica gel column (product name: Hi-Flash Column 3 L, manufactured by Yamazen Corporation) to afford the title compound (9.11 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[O:28](S(C(F)(F)F)(=O)=O)[S:29]([C:32]([F:35])([F:34])[F:33])(=O)=[O:30].O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:30])=[O:28])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OS(=O)(=O)C(F)(F)F)C1
Temperature: 25 °C
Yield: 38.7 %

Procedure:
To 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (2.0 g, 6.7 mmol) in CH2Cl2 (34 mL) at 0° C. was added Et3N (0.74 g, 1.0 mL, 7.3 mmol) and Tf2O (2.0 g, 7.0 mmol). After warming to rt, H2O was added and the mixture extracted with CH2Cl2 (2×). The combined organics were dried. Silica gel chromatography (5-25%) gave 1.12 g (39%) of the title compound as a white solid. 1H NMR (CDCl3): 7.20 (d, J=8.7 Hz, 1H), 7.03 (dd, J=8.7, 2.3 Hz, 1H), 6.67 (d, J=2.3 Hz, 1H), 4.95-4.91 (m, 1H), 4.34 (ddd, J=10.0, 6.4, 1.0 Hz, 2H), 4.08-4.04 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])=[C:16]([CH:26]([CH3:28])[CH3:27])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[K+].[K+].[Si:35]([O:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47]Br)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>CN(C)C=O>[Si:35]([O:42][CH2:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][CH:51]=1)[CH2:47][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]1[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14][NH:15][C:16]=1[CH:26]([CH3:28])[CH3:27])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(CBr)c1
Reactant: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccccc1OCc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 20 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-4-(2-hydroxybenzyl)-5-isopropyl-1H-pyrazole (164 mg) and potassium carbonate (115 mg) in N,N-dimethylformamide (5 mL) was added 3-tert-butyldimethylsilyloxymethylbenzyl bromide (197 mg) at room temperature, and the mixture was stirred for 20 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1-10/1–5/1) to give 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole. To a solution of the obtained 4-[2-(3-tert-butyldimethylsilyloxymethylbenzyloxy)benzyl]-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole in tetrahydrofuran (2 mL) was added tetra-(n-butyl)ammonium fluoride (1 mol/L tetrahydrofuran solution, 0.065 mL) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (22 mg).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33]>O1CCOCC1>[CH3:33][C:32]1[O:31][C:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[N:29][C:28]=1[CH2:27][S:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[C:20]([OH:22])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1Cc2ccccc2N1S(=O)(=O)c1ccc(S)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CSc1ccc(S(=O)(=O)N2c3ccccc3C[C@@H]2C(=O)O)cc1
Reaction time: 1.5 h
Yield: 80.4 %

Procedure:
To a solution of the title D compound, (R)-1-(4-mercapto-benzenesulfonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (0.56 g, 1.67 mmol) in dioxane (8 mL) is added 1N aqueous sodium hydroxide (3.4 mL) and water (2 mL) at room temperature. The resulting solution is treated dropwise with a solution of 4-chloromethyl-5-methyl-2-phenyl-oxazole (0.423 g, 2.04 mmol) in dioxane (4 mL). After stirring 1.5 hours, the reaction mixture is concentrated to near dryness in vacua. The residue is taken into water, the aqueous phase is washed with ether, acidified with 2N aqueous hydrochloric acid and extracted into ethyl acetate. The combined organic phases are washed with water, brine and dried over sodium sulfate. The organic phase is concentrated in vacuo and dried overnight at high vacuum to give 0.68 g of (R)-1-[4-(5-methyl-2-phenyl-oxazol-4-ylmethylsulfanyl)-benzenesulfonyl]-2,3-dihydro-1H-indole-2-carboxylic acid as gum: [M−1]−=504.9.
Reaction SMILES: [C:1]([CH:3]([OH:15])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1)#[N:2].B.CO.[ClH:19]>O1CCCC1>[ClH:19].[NH2:2][CH2:1][CH:3]([OH:15])[C:4]1[C:9]([F:10])=[CH:8][C:7]([O:11][CH3:12])=[C:6]([O:13][CH3:14])[CH:5]=1
Reactant: COc1cc(F)c(C(O)C#N)cc1OC
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(F)c(C(O)CN)cc1OC

Procedure:
To a suspension of 3.24 g α-(cyano)-6-fluoro-3,4-dimethoxybenzyl alcohol obtained in Reference Example 1 in 20 ml tetrahydrofuran, was added dropwise 33 ml of 1M solution of borane in tetrahydrofuran with stirring in a methanol/ice bath under an argon gas atmosphere, and the resulting solution was heated under reflux for three hours. After cooling the reaction mixture in an ice bath, methanol was added until gas evolution was no longer observed, the resulting solution was stirred at room temperature for one hour, and hydrogen chloride gas was introduced until the pH fell below 1. The crystals which separated out were collected, affording 3.34 g of α-(aminomethyl)-6-fluoro-3,4-dimethoxybenzyl alcohol hydrochloride, m.p. 223°-226° C.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[F:15][C:16]1[CH:44]=[CH:43][CH:42]=[CH:41][C:17]=1[C:18]([N:20]1[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH:21]1[CH2:33][O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:19]>CO>[ClH:1].[ClH:1].[F:15][C:16]1[CH:44]=[CH:43][CH:42]=[CH:41][C:17]=1[C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH:21]1[CH2:33][O:34][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2F)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccccc1F)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 86 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(2-fluorobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (26 mg, 0.050 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane. This was concentrated under reduced pressure, yielding 16.3 mg (86%) of the title compound as an off-white solid. LC-MS: RT=3.00 min, [M+H]+=316.3.
Reaction SMILES: BrBr.[OH-].[K+].[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:16])C)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.[O-:17]S([O-])(=S)=O.[Na+].[Na+].Cl>O>[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=[O:17])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: CC(=O)c1ccc2c(c1)CCC2
Reactant: O=S([O-])([O-])=S
Agent: BrBr
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)CCC2
Temperature: 55 °C

Procedure:
Bromine (20.5 mL, 0.4 mol) was added to a solution of KOH (72.9 g, 1.3 mol) in water (250 mL) at 0° C. To the resulting solution was slowly added compound 2 (16.0 g, 0.1 mol) at 0° C. The reaction mixture was heated at 55° C. overnight and quenched with Na2S2O3 (14.8 g, 0.094 mol). The mixture was acidified to pH 2-3 with conc. HCl (40˜50 mL). The precipitate was collected by filtration, and washed with water. The crude product 3 was dried under high vacuum and used without further purification (15.4 g, 0.095 mol, 95%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Br:14]N1C(C)(C)C(=O)N(Br)C1=O.OS([O-])=O.[Na+].CCOC(C)=O>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Br:14]
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(Cl)c(F)c(N)c1Br
Temperature: 83 °C
Yield: 60.5 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (1.0 g, 4.9 mmol) was combined with 1,3-dibromo-5,5-dimethylhydantoin (1.7 g, 5.9 mmol) in 1,2-dichloroethane (15 mL) and heated at reflux (83° C.) for 4 h. The cooled mixture was stirred with 10% NaHSO3 solution and EtOAc (30 mL). The organic phase was separated, washed with water (2×20 mL), brine (10 mL), dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (5-50% EtOAc-hexane) to give an orange solid (840 mg, 61%): mp 138-139° C.; EIMS m/z 282, 284; 1H NMR (400 MHz, CDCl3) δ 5.09 (s, 2H, NH2), 3.97 (s, 3H, Me); 19F NMR (376 MHz, CDCl3) δ −135.55 (s).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>>[CH2:30]([S:33]([N:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:35])=[O:34])[CH2:31][CH3:32]
Reactant: CCCS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@@H]3CCNC3)cnc21
Product: CCCS(=O)(=O)N1CC[C@@H](Nc2ncccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
[(R)-1-(Propane-1-sulfonyl)-pyrrolidin-3-yl]-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (R)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and propane-1-sulfonyl chloride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=[C:4]2[N:3]1[CH2:15][C:16]([OH:18])=O.[Br:19][C:20]1[C:21]([C:26]2[NH:30][N:29]=[CH:28][N:27]=2)=[C:22]([NH2:25])[S:23][CH:24]=1>>[Br:19][C:20]1[C:21]([C:26]2[NH:30][N:29]=[CH:28][N:27]=2)=[C:22]([NH:25][C:16](=[O:18])[CH2:15][N:3]2[C:2](=[O:1])[CH:7]=[CH:6][N:5]3[N:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=[C:4]23)[S:23][CH:24]=1
Reactant: O=C(O)Cn1c(=O)ccn2nc(C(F)(F)F)cc12
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(Cn1c(=O)ccn2nc(C(F)(F)F)cc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(5-oxo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-4(5H)-yl)acetic acid (63 mg, 0.244 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (30 mg, 0.122 mmol) according to protocol A. Retention time (min)=4.975, method [7], MS (ESI) 488.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.79 (d, J=7.4 Hz, 1H), 8.61 (bs, 1H), 7.32 (s, 1H), 6.96 (s, 1H), 6.45 (d, J=7.4 Hz, 1H), 5.01 (s, 2H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[OH-].[Na+].[C:12](Cl)(=[O:15])[CH2:13][CH3:14]>C1COCC1>[C:12]([NH:1][C@H:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1)(=[O:15])[CH2:13][CH3:14]
Reactant: N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Temperature: 25 °C

Procedure:
100.0 mg (0.77 mmol) (1R,3S)-3-Aminocyclopentane carboxylic acid is stirred in 2.0 mL THF and 0.77 mL (1.55 mmol) sodium hydroxide solution (2 mol/l). 74.0 μL (0.85 mmol) Propionyl chloride is added drop wise and the mixture is stirred at RT over night. The solvent is evaporated. The mixture is stirred at RT over night. The product is purified by RP-HPLC (water+5-95% acetonitrile (with addition of 0.1% TFA)) and lyophilized.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N+]=[N-].[H][H]>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13]
Reactant: [H][H]
Reactant: CCOP(=O)(CCCN=[N+]=[N-])OCC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOP(=O)(CCCN)OCC
Reaction time: 3 h

Procedure:
Diethyl 3-azidopropylphosphonate (1 eq) was dissolved in EtOH (0.1 M). Pd(OH)2 (0.02 eq) was added to the reaction. Hydrogen gas was introduced via a balloon and the reaction was stirred for 3 hours. The reaction was stirred for a further 2 hours at room temperature and filtered through Celite and washed with methanol. The solvent was removed en vaccuo and the crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% MeOH in DCM with 0.5% NH3 in MeOH to give the product as colorless oil.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]2[S:14][CH2:13][C:12]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[N:11]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:5]([CH2:24][CH3:25])[CH:4]=1)=O.[N+:26]([CH3:29])([O-:28])=[O:27]>>[CH2:24]([C:5]1[CH:4]=[C:3](/[CH:1]=[CH:29]/[N+:26]([O-:28])=[O:27])[CH:8]=[CH:7][C:6]=1[N:9]=[C:10]1[S:14][CH2:13][C:12]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[N:11]1[CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]1)[CH3:25]
Reactant: C[N+](=O)[O-]
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Product: CCc1cc(/C=C/[N+](=O)[O-])ccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 4-cyano-2-ethylphenyl isothiocyanate according to Method C1e to give 2-(4-cyano-2-ethylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(4-cyano-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The nitrile was reduced according to Method D11a to give 2-(4-formyl-2-ethylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane. The aldehyde was reacted with nitromethane according to Method D12b according to afford 2-(2-ethyl-4-((1E)-2-nitrovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[C:11](=S)[C@H:10]2[F:23])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>O1CCCC1.[Ni]>[CH2:1]([O:3][C:4]([C:6]1([C@H:9]2[CH2:13][N:12]([C@H:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH3:15])[CH2:11][C@H:10]2[F:23])[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C(=S)[C@H]2F)CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)C1([C@H]2CN([C@@H](C)c3ccccc3)C[C@H]2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
4-(S)-(1-Ethoxycarbonylcyclopropyl)-3-(S)-fluoro-1-[1-(S)-phenylethyl]-2-pyrrolidinethione (6.49 g, 19.35 mmol) was dissolved in anhydrous tetrahydrofuran (150 ml), and the solution was mixed with Raney nickel (15 ml) and stirred at room temperature for 30 minutes. After removing the catalyst by celite filtration (tetrahydrofuran washing), the resulting filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in diethyl ether (200 ml), washed with 10% ammonia water (200 ml×2) and saturated brine (150 ml) in that order and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5.08 g (86.0%) of the title compound as a colorless oil.
Reaction SMILES: CO.[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C@@H:5]([CH2:7][CH3:8])[CH3:6].[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22]O)[OH:21])[OH:19])[OH:17])[OH:15]>N1C=CC=CC=1>[CH2:22]([NH:3][C@@H:4]([C:9]([OH:11])=[O:10])[C@@H:5]([CH2:7][CH3:8])[CH3:6])[C:20]1([O:12][CH2:13][C@@H:14]([OH:15])[C@@H:16]([OH:17])[C@@H:18]1[OH:19])[OH:21]
Reactant: CC[C@@H](C)[C@@H](N)C(=O)O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: c1ccncc1
Solvent: CO
Product: CC[C@@H](C)[C@@H](NCC1(O)OC[C@@H](O)[C@@H](O)[C@@H]1O)C(=O)O
Yield: 49.2 %

Procedure:
A dry mixture of 40 ml of methanol and 10 ml of pyridine was added to 100 mg of dry D-isoleucine together with 300 mg of anhydrous glucose, and reaction and purification were carried out as described in Example 9, but making use of smaller-volume chromatography columns. Crystallization of the final product yielded 110 mg of N-(1-deoxyfructopyranos-1-yl)-D-isoleucine. Melting point 142°-144° C.