Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][NH:11]2)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:11]1[CH2:10][C@@H:9]2[CH2:14][C@H:12]1[CH2:13][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1ccccn1
Temperature: 85 °C
Yield: 49 %

Procedure:
A mixture of BINAP (31 mg, 0.05 mmol) and Pd2dba3 (230 mg, 0.03 mmol) were taken in toluene and the solution was heated to 85° C. for 10 min under argon atmosphere. The solution was cooled to 40° C. and (1S,4S)-2-boc-2,5-diazabicyclo[2.2.1]heptane (250 mg, 1.26 mmol) was added, followed by 2-bromo pyridine (218 mg, 1.38 mmol) and sodium tert-butoxide (194 mg, 2.0 mmol). The reaction mixture was heated to 85° C. for 5 h, cooled to room temperature, diluted with EtOAc and filtered through Celite. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 20-30% EtOAc in petroleum ether) to get (1S,4S)-tert-butyl 5-(pyridin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (170 mg, yield 49%). 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=4.6 Hz, 1H), 7.47-7.42 (t, J=7.7 Hz, 1H), 6.59-6.55 (m, 1H), 6.35-6.32 (d, J=8.6 Hz, 1H), 4.90-4.79 (m, 1H), 4.67-4.52 (m, 1H), 3.57-3.35 (m, 4H), 1.96-1.92 (m, 2H), 1.46-1.42 (m, 9H). MS (ESI) m/z: Calculated for C15H21N3O2: 275.16. found: 276.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[C:5]([CH3:15])=[CH:4][N:3]=1.C([O:18][CH:19]=[C:20]([C:26](OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>CN(C)C=O>[CH3:15][C:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[C:2]2=[N:1][CH:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:18])[N:3]2[CH:4]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cnc(N)c2cc([N+](=O)[O-])ccc12
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c3cc([N+](=O)[O-])ccc3c(C)cn2c1=O
Temperature: 120 °C
Reaction time: 4 h
Yield: 67.5 %

Procedure:
A mixture of 1-amino-4-methyl-7-nitroisoquinoline (3.87 g), diethyl ethoxymethylenemalonate (4.53 g) in N,N-dimethylformamide (20 ml) was heated at 120° C. with stirring for 4 hours. Additional diethyl ethoxymethylenemalonate (1 g) was added to the mixture, and then the reaction mixture was refluxed for 18 hours and cooled to give precipitate. The crystals obtained were filtered off and washed with cold ethanol to give ethyl 7-methyl-10-nitro-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (4.21 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][N:6]=1
Reactant: OB(O)C1CC1
Reactant: Clc1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Clc1ccc(C2CC2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a suspension of 5-bromo-2-chloropyridine (990 mg, 5.15 mmol), cyclopropylboronic acid (893 mg, 10.39 mmol) and Cs2CO3 (5.082 g, 15.45 mmol) in 1,4-dioxane (25 mL) was added Pd(PPh3)4 (601 mg, 0.52 mmol) at r.t. under N2. The reaction was stirred at 100° C. for 1 h. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc=50:1) to give 452 mg (57%) of the title compound as a colorless oil. [M+H] Calc'd for C8H8NCl, 154. Found, 154.
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[Na+].Cl>C1COCC1.O>[CH3:11][Si:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:4]=[C:3]([Si:2]([CH3:16])([CH3:1])[CH3:17])[CH:8]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cc([Si](C)(C)C)cc([Si](C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)c1cc(C(=O)C=Cc2ccc(C(=O)O)cc2)cc([Si](C)(C)C)c1
Yield: 65.7 %

Procedure:
Under ice-cooling, to a solution of 114 mg (0.43 mmol) of 3',5'-bis(trimethylsilyl)acetophenone and 70 mg (0.43 mmol) of methyl 4-formylbenzoate in 3 ml of THF was added a solution of 40 mg (1.00 mmol) of NaOH in 2 ml of H2O with stirring, and the mixture was stirred in an atmosphere of prepurified argon overnight. The reaction mixture was further added to 39 mg of NaOH, stirred for 2 days, and then the solution was adjusted with 2N-HCl to pH≤7 and extracted with ethyl acetate. The extract was dried and evaporated. The residue was purified by column chromatography using methylene chloride-methanol (10:1) as an eluant to give 112 mg of the desired compound (yield 66%), which was recrystallized from a mixture of ethyl acetate and n-hexane to give 98 mg of pale yellow prisms, m.p. 194°-195.5° C. (yield 57%).
Reaction SMILES: [C:1]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:13][C:14]([C:16]2([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:9]([O:11]C)=[O:10])=[CH:3][CH:2]=1.CCCC[Sn](O[Sn](CCCC)(CCCC)CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[C:1]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:13][C:14]([C:16]2([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:15])[C:9]([OH:11])=[O:10])=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC1(C(=O)N[C@H](Cc2ccc(-c3ccccc3)cc2)C(=O)OC)CCCC1
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=C(O)CC1(C(=O)N[C@H](Cc2ccc(-c3ccccc3)cc2)C(=O)O)CCCC1
Temperature: 90 °C
Reaction time: 15 h
Yield: 10.1 %

Procedure:
To a solution of (R)-methyl 3-(biphenyl-4-yl)-2-(1-(2-ethoxy-2-oxoethyl)cyclopentanecarboxamido)propanoate (135.5 mg, 0.310 mmol) in toluene (3.1 ml), bis(tributyltin) oxide (1.578 ml, 3.10 mmol) was added at room temperature under nitrogen. The reaction mixture was allowed to stir at 90° C. for 15 hr and then 100° C. for 26 hr. The reaction mixture was cooled to room temperature, 10% KFaq (2 ml) was added. The suspension was vigorously stirred for 1 hr, the solution was filtered, and the organic layer and the aqueous layer were separated. To the aqueous layer, 10% citric acid aq was added. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and the obtained product was treated with 1M LiOH (0.5 ml) in THF (0.5 ml) and MeOH (0.1 ml) for 17 hr. The reaction mixture was acidified with 1M HCl to pH 3. The product was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified twice by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) and then solidified in DCM/heptane to give (R)-3-(biphenyl-4-yl)-2-(1-(carboxymethyl)cyclopentanecarboxamido)propanoic acid (12.4 mg); Retention time=1.63 minutes (condition A); MS (m+1)=396.0; 1H NMR (400 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.45-1.50 (m, 6H) 1.95-2.00 (m, 2H) 2.39-2.62 (m, 2H) 2.84-3.12 (m, 2H) 4.40-4.46 (m, 1H) 7.30-8.15 (m, 10H) 12.25 (br s, 2H); HRMS (ES+) m/z for C23H25NNaO5 [M+Na]+ calcd 418.16304. found 418.1632.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH3:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[C:11]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])=[O:12]>>[CH3:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[C:11]([O:13][CH2:14][CH2:15][O:16][C:17]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:18])=[O:12]
Reactant: NC1(C(=O)O)CC1
Reactant: Cc1ccccc1C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: Cc1ccccc1C(=O)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 43.3 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (121 mg, 1.2 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylbenzoate (321 mg, 1.0 mmol) were reacted to provide 133 mg (43% yield) of the title compound (3) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=7.85 (d, 1H), 7.40 (t, 1H), 7.21 (t, 2H), 7.01 (q, 1H), 5.79 (br s, 0.3H), 5.41 (s, 0.7H), 2.58 (s, 3H), 1.60 (m, 5H), 1.30 (m, 2H). MS (ESI) m/z 325.17 (M+NH4)+; 330.12 (M+Na)+; 306.15 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[Si](C)(C)C)=[O:5])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][O:8][C:7]=1[Cl:18])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccoc1[Si](C)(C)C
Solvent: CC#N
Product: CCOC(=O)c1ccoc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
2-Trimethylsilyl-3-furancarboxylic acid (16.4 g) (synthesized in accordance with the method described in J. C. S. Perkin, 1, 1125 (1981)) was dissolved in N,N-dimethylformamide (50 ml), and potassium carbonate (12.3 g) and iodoethane (13.9 g) were added. The mixture was stirred at room temperature for 15 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) as oil. 2-Trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) was dissolved in acetonitrile (75 ml), and sulfuryl chloride (10.9 g) in acetonitrile (25 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-chloro-3-furancarboxylic acid ethyl ester (3.5 g) as oil. 2-Chloro-3-furancarboxylic acid ethyl ester (3.5 g) was dissolved in ethanol (25 ml), and 1N aqueous sodium hydroxide (25 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with diisopropyl ether-hexane to give 2-chloro-3-furancarboxylic acid (2.2 g) as crystals. mp 138°-141° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1>C(O)C>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4]
Reactant: Brc1nccs1
Reactant: OCCNCCO
Solvent: CCO
Product: OCCN(CCO)c1nccs1
Yield: 24.7 %

Procedure:
In a sealable tube were successively added diethanolamine (3.46 mL, 35.8 mmol) and 2-bromothiazole (1.538 mL, 17.07 mmol), under nitrogen. The tube was sealed and the mixture was irradiated in the microwave at 130° C. for 30 min. The residue was dissolved in 5:95 ethanol:dichloromethane and chromatographed on silica (CombiFlash, 5-20%, ethanol in dichloromethane) to afford 2,2′-(1,3-thiazol-2-ylimino)diethanol (795 mg, 4.22 mmol, 24.74% yield) as a pale oil.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH:8]([NH:10][C:11](=O)[CH3:12])[CH3:9])=[N:6][N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:3]1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:9][C:8]1[N:10]=[C:11]([CH3:12])[N:6]2[C:7]=1[C:2](=[O:1])[NH:3][C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:5]2
Reactant: CC(=O)NC(C)c1nnc(-c2ccccc2)[nH]c1=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(C)n2nc(-c3ccccc3)[nH]c(=O)c12

Procedure:
8.34 g (32.3 mmol) of N-[1-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazin-6-yl)ethyl]acetamide] (Example 14A) were dissolved in 330 ml of 1,2-dichloroethane and 4.5 ml (48.5 mmol) of phosphoryl chloride were added. The mixture was stirred under reflux for 24 h. After cooling, the precipitate was filtered off and washed with water and diethyl ether. The product was subsequently dried under high vacuum. This gave 4.6 g (59% of theory) of the product as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](OCC)=O)[CH2:17][CH2:16]3)[C:6]=2[CH2:26][O:27][CH3:28])[CH2:3][CH2:2]1>C(O)C.O>[CH:1]1([NH:4][C:5]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[C:7]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[C:6]=2[CH2:26][O:27][CH3:28])[CH2:2][CH2:3]1
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(NC3CC3)c2COC)CC1
Solvent: CCO
Solvent: O
Product: COCc1c(NC2CC2)c([N+](=O)[O-])cc(F)c1N1CCN(C)CC1

Procedure:
N-Cyclopropyl-2-methoxymethyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline, orange red needles, m.p. 89°-90° C. (ethanol-water)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:12][NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:12]([CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[NH:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=Cc1cccnc1
Reactant: O=C1NNC(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C1NN(Cc2cccnc2)C(c2ccncc2)C1c1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(3,4-Dichloro-phenyl)-5-pyridin-4-yl-pyrazolidin-3-one 0.30 g and 0.12 mL 3-pyridinecarboxaldehyde in chloroform 20 mL was added NaBH3(CN) 0.1 g at 0° C., the reaction was warmed 50° C. and stirred for 1 hour. The reaction was quenched with sat.NaHCO3 25 mL at 0° C. The reaction mixture was extracted with dichloromethane, 3×50 mL. The combined organic phase was washed with brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as yellow solid 0.28 g. MS (ES+): 399 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([O:32][CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:18]1[CH:19]=[C:20]([S:24][CH2:25][CH2:26]OS(C)(=O)=O)[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[CH3:39][N:36]1[CH2:37][CH2:38][CH:33]([O:32][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24][CH2:25][CH2:26][N:2]3[N:3]=[CH:4][CH:5]=[N:1]3)[CH:19]=2)[C:9]2[S:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:34][CH2:35]1
Reactant: CN1CCC(OC(c2cccc(SCCOS(C)(=O)=O)c2)c2nc3ccccc3s2)CC1
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCC(OC(c2cccc(SCCn3nccn3)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,2,3-triazole (36.5 mg) in N,N-dimethylformamide (1 mL) is added a dispersion of sodium hydride 60% in mineral oil (1 molar equivalent). The reaction mixture is stirred at room temperature for 15 minutes, then a solution of methanesulfonic acid 2-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl ester (85 mg) in N,N-dimethylformamide (1 mL) is added. The reaction mixture is stirred at 60° C. overnight. Water is added and the aqueous phase is extracted by ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography (gradient dichloromethane/methanol/ammonia 100/0/0 to 90/10/1) to afford 2-{(1-methylpiperidin-4-yloxy)[3-(2-[1,2,3]triazol-2-yl-ethylsulfanyl)phenyl]methyl}benzothiazole.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2-:6][C:7]([CH3:9])=[O:8].[CH:10]([NH:13][CH2:14][C@H:15]([OH:18])[CH2:16][OH:17])([CH3:12])[CH3:11].C(N(CC)CC)C>O1CCCC1.[Cl-].[Na+].O>[CH2-:6][C:7]([CH3:9])=[O:8].[S:1]([N:13]([CH:10]([CH3:12])[CH3:11])[CH2:14][C@H:15]([OH:18])[CH2:16][OH:17])([CH3:4])(=[O:3])=[O:2]
Reactant: CC(C)NC[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: [CH2-]C(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C[C@H](O)CO)S(C)(=O)=O

Procedure:
90 ml mesyl chloride was added with stirring to a previously chilled (-10°) solution of (2S)-3-isopropylamino-1,2-propanediol acetonide (188 g; 1.087 mol) and triethylamine (228 ml; 1.63 mol) in dry tetrahydrofuran at such a rate that the reaction temperature did not exceed 5°. Reaction was then stirred at 10°-15° for 30 minutes whereupon it was diluted with 1.5 L brine. The layers were separated and the aqueous layers were extracted with ether (3×500 ml). The organic layers were washed in turn with brine (2×500 ml) and then were combined, dried over sodium sulfate, and evaporated to give 264 g of (2S)-3-[N-mesyl-(1-methylethyl)amino]-1,2-propanediol acetonide as an oil.
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:22])=O)[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.CN(C(ON1N=[N:55][C:50]2C=[CH:52][CH:53]=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCNCC1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:29][CH2:30][CH:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH2:32][CH2:33]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20]([N:54]3[CH2:49][CH2:50][NH:55][CH2:52][CH2:53]3)=[O:22])[CH2:16][CH2:15]2)=[O:7])=[CH:38][CH:39]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)O)CC4)c3c2)CC1
Agent: C1CNCCN1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(O)C1CCN(Cc2ccc3[nH]/c(=N\C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)N5CCNCC5)CC4)c3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of cis-4-((E)-2-(4-fluorobenzoylimino)-6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylic acid (100 mg, 0.186 mmol) in DMF (3 mL) was added HATU (74.4 mg, 0.196 mmol) and DIPEA (0.036 mL, 0.205 mmol). The suspension was stirred for 15 minutes at RT. A solution of piperazine (161 mg, 1.863 mmol) in DMF (1 mL) was added, and the reaction was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc. The organic layer was concentrated and the residue purified by HPLC (15-90% ACN/0.1% TFA). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-(cis-4-(piperazine-1-carbonyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide as a white powder (67 mg, 59.5% yield). MS, m/z (C34H45FN6O3): calcd, 604.3. found, 605.1 [M+H].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.[CH2:17]1C[O:20][CH2:19][CH2:18]1>BrCCCO>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][N:11]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:10]3)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: C1CCOC1
Agent: OCCCBr
Product: OCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep4, 151 mg) in dry THF (3.3 mL), TEA (0.112 mL) and 3-bromo-1-propanol (0.073 mL) were added and the resulting mixture was heated at reflux for 4 hours. After cooling at room temperature it was diluted with EtAcO (20 mL), washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by a silica SPE cartridge (10 g) eluting with DCM/MeOH from 99/1 to 96/4 to give the title compound as a colourless oil (143 mg).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=[CH:9][C@@H:10]([C@H:12]([C@@H:14]([C@@H:16]([CH2:18][OH:19])[OH:17])[OH:15])[OH:13])[OH:11]>ClCCl>[CH2:4]1[CH2:5][CH2:6][C:1]2([O:11][CH:10]([C@H:12]3[O:13][C@@H:18]4[O:19][C:1]5([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[O:17][C@@H:16]4[C@H:14]3[OH:15])[CH2:9][O:7]2)[CH2:2][CH2:3]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1CCCCC1
Solvent: ClCCl
Product: O[C@@H]1[C@H]2OC3(CCCCC3)O[C@H]2O[C@@H]1C1COC2(CCCCC2)O1
Temperature: 63 °C
Reaction time: 8.5 h
Yield: 51 %

Procedure:
To a mixed solution of 150 ml of cyclohexanone and 120 ml of dichloromethane were added 10.0 g of D-glucose and 125 mg of anhydrous cupric chloride, and the mixture was stirred for 8.5 hours under reflux in a warm-water bath at 63° C. The refluxing solvent was continuously dried with 20 g of molecular sieves 3A which was placed between the reaction vessel and the cooling tube. The reaction solution was diluted with chloroform, washed with aqueous sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent and cyclohexanone were distilled off under reduced pressure, and the residue was recrystallized from ligroin, thus affording 9.6 g (51%) of 1,2:5,6-di-O-cyclohexylidene-α-D-glucofuranose. m.p. 133°-136° C.