Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].CC1(C)C(C)(C)OB([C:34]2[CH:35]=[C:36]([C:40]3([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:42][CH2:41]3)[CH:37]=[CH:38][CH:39]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:38]5[CH:37]=[C:36]([C:40]6([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:42][CH2:41]6)[CH:35]=[CH:34][CH:39]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
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: [K+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C2(NC(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (110 mg, 0.300 mmol) was dissolved in 3 mL of 1,2-dimethoxyethane (DME) in a microwave reactor tube. tert-Butyl 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropylcarbamate (50% pure, 280 mg, 0.390 mmol), 0.4 mL of an aqueous 2 M potassium carbonate solution, and tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4, 17 mg, 0.015 mmol) were added and the reaction mixture was heated at 120° C. in a microwave reactor for 20 minutes. The resulting material was cooled to room temperature, filtered, and the layers were separated. The organic layer was evaporated to dryness and the residue was purified on silica gel utilizing a gradient of 0-30% ethyl acetate in hexanes to yield tert-butyl 1-(3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)phenyl)cyclopropylcarbamate. This material was then dissolved in 3 mL of dichloromethane containing 1 mL of trifluoroacetic acid (TFA) and was allowed to stir for 15 min at room temperature. The mixture was evaporated to dryness, dissolved in a minimum of N,N-dimethylformamide, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield N-(6-(3-(1-aminocyclopropyl)phenyl)-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 463.2, found; 464.0 (M+1)+ Retention time 1.39 minutes.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][N:9]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]2=[N:7][CH:8]=1)[NH2:2].C(Cl)Cl.[C:25]([O:29][C:30]([NH:32][CH:33]1[CH2:37][CH:36]([C:38](O)=[O:39])[CH:35]([CH2:41][CH3:42])[CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH:33]1[CH2:37][CH:36]([C:38]([NH:2][NH:1][C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]([S:12]([C:15]4[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[C:6]3=[N:7][CH:8]=2)=[O:39])[CH:35]([CH2:41][CH3:42])[CH2:34]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCC1CC(NC(=O)OC(C)(C)C)CC1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
A round-bottomed flask was charged with 2-hydrazinyl-5-tosyl-5H-pyrrolo[2,3-b]pyrazine (2.0 g, 6.6 mmol, Step J) and DCM (40 mL) to give a brown suspension. 4-(tert-Butoxycarbonylamino)-2-ethylcyclopentanecarboxylic acid (2.0 g, 7.8 mmol, Step G), HATU (2.51 g, 6.59 mmol), and TEA (4.59 mL, 33.0 mmol) were added to the suspension and the resulting mixture was stirred at ambient temperature for about 24 h with dissolution occurring after about 2 h. Water (20 mL) was added and the layers were partitioned. The organic layer was washed with additional water (2×15 mL), brine (2×25 mL), dried over anhydrous MgSO4, filtered, and solvent was removed under reduced pressure to give a brown residue. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM. The recovered impure material was re-purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM. The product-containing fractions from the two columns were combined and concentrated to give tert-butyl-3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)cyclopentylcarbamate (2.45, 69%) as a brown solid: LC/MS (Table 2, Method d) Rt=1.47 min; MS m/z: 543 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([N:6]1[CH2:11][CH2:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[C:3]([O-:5])=[O:4].[OH:22][S:23]([OH:26])(=[O:25])=[O:24]>CC(C)=O>[S:23](=[O:24])(=[O:22])([OH:26])[OH:25].[CH3:1][C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([N:6]1[CH2:11][CH2:10][C:9]2[S:12][CH:13]=[CH:14][C:8]=2[CH2:7]1)[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)[O-])(c1ccccc1Cl)N1CCc2sccc2C1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(C(=O)O)(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 27.5 °C

Procedure:
To 1.98 g (+)-Methyl(2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetate was added 5 mL of acetone and stirred at 25-30° C. The temperature of the reaction mixture was raised from 25 to 50-52° C. and within one lot 0.7 g of concentrated H2SO4 (95%) was added with constant stirring and the reaction mixture was suddenly cooled to 0° C. to −5° C. for 10 min. Later the reaction mixture was stirred at 25-30° C. for 12 hrs, the thick precipitate obtained was filtered, washed with 5 mL of acetone and the residue (1.6 g, 62%) was dried in a vacuum oven.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CN1CCOCC1.Cl[C:28]([O:30][CH:31]([Cl:35])[CH:32]([CH3:34])[CH3:33])=[O:29]>ClCCl>[Cl:35][CH:31]([O:30][C:28]([NH:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:29])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)CC(CN)CC(=O)OCc1ccccc1
Reactant: CC(C)C(Cl)OC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC(CNC(=O)OC(Cl)C(C)C)CC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of (39) (594 mg, 2.38 mmol) in dichloromethane at 0° C. was added N-methylmorpholine (0.523 mL, 4.77 mmol) and 1-chloro-2-methylpropyl chloroformate (0.347 mL, 2.38 mmol). The resulting solution was stirred at 0° C. until the reaction was complete (˜30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1N HCl solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (42) as a mixture of two diastereomers (840 mg, 92%), which was used without further purification in the following example. 1H-NMR (CDCl3, 400 MHz): δ 0.86 (2 d, 6H), 1.02 (2 d, 6H), 1.15 (m, 2H), 1.63 (m, 1H), 2.14 (m, 2H), 2.34 (m, 2H), 3.10 (m, 1H), 3.28 (m, 1H), 5.11 (br.s, 3H), 6.29 (d, 1H), 7.31 (m, 5H).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=O)=[O:4].C(N(CC)CC)C.ClC(OCC)=O.[NH2:30][C@H:31]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl>CN(C=O)C>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:30][C@H:31]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH3:50])=[O:48])[CH2:43][CH2:44][S:45][CH3:46])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:9])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: COC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.43 g of Boc-Gly-Gly-OH, A (2) is dissolved in 30 ml DMF and cooled to 0° C., after which 1 equivalent TEA (triethylamine) is added. The mixture is cooled further to about -10° C., after which 1 equivalent (eq) ethyl chloroformate is added and the whole is stirred for about 10 minutes. 6.6 g H-Phe-Met-OMe.HCl (A.1) in 30 ml DMF and 1.1 eq TEA is then added to the mixture, which is stirred for about 30 minutes at about -10° C. and for a further 20 hours at room temperature. After cooling to about -10° C., TEA.HCl is separated by filtration and the filtrate is evaporated to dryness. The residue is dissolved in 235 ml EtOAc and 55 ml water and is subsequently washed with 30% NaCl solution, 0.1 N HCl, 30% NaCl solution, 5% NaHCO3 solution and 30% NaCl solution. The solution is then dried over Na2SO4 filtered and evaporated to dryness. Melting point 100°-101° C.; Rf in CHCl3 :CH3OH:Wa (70:30:5)=0.94 on SiO2.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][CH2:17][CH2:18]Br)[CH3:15]>>[C:1]1([CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][CH2:14][O:16][CH2:17][CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCCBr
Reactant: c1ccc(Cc2ccccc2)cc1
Product: CCOCCC(c1ccccc1)c1ccccc1

Procedure:
According to a second process disclosed by Sperber (loc. cit.) diphenylmethane is reacted with 2-bromoethyl ethyl ether to yield 3,3-diphenyl-1-ethoxypropane. Alkylation of 3,3-diphenyl-1-ethoxypropane with 2-dimethylaminoethyl chloride yielded 5-ethoxy-3,3-diphenyl-N,N-dimethylamylamine; cleavage of the ethoxy group gave 5-hydroxy-3,3-diphenyl-N,N-dimethylamylamine hydrobromide, which was reacted with thionyl chloride to give 4,4-diphenyl-1,1-dimethylpiperidinium chloride, from which sublimation in vacuo yielded 1-methyl-4,4-diphenylpiperidine. This synthesis includes 5 reaction steps and provides an overall maximum yield of about 23 percent of theory. The availability of this synthesis for the preparation of homologues of 1-methyl-4,4-diphenylpiperidine, e.g. of 1-ethyl-4,4-diphenylpiperidine or 1-isopropyl-4,4-diphenylpiperidine has to be regarded as doubtful.
Reaction SMILES: O=P(Cl)(Cl)Cl.C([O:8][CH:9](OCC)[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]([CH3:33])[CH:31]=O>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][C:10](=[CH:29][N:30]([CH3:33])[CH3:31])[CH:9]=[O:8]
Reactant: CN(C)C=O
Reactant: CCOC(COc1ccc(Cl)c(Cl)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)Oc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Dimethylformamide (29.2 g) was slowly added to 122.7 g of POCl3 in a reaction flask. After the addition was complete, the mixture was heated to 80° C. while 3,4-dichlorophenoxyacetaldehyde diethyl acetal (55.8 g) was added, and the resulting mixture was then heated for an additional two hours at about 80°-85° C. The reaction mixture was cooled to room temperature and poured into about 400 g of potassium carbonate in an ice-water mixture and then extracted with methylene chloride. The methylene chloride extract was then dried and concentrated to a dark oil which solidified upon dilution with ethyl acetate. 22.1 g of the desired, 2-(3,4-dichlorophenoxy)-3-dimethylamino-propenal was obtained and subsequently identified by NMR spectroscopy.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([C@H:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19])C1C=CC=CC=1.C(O)(C(F)(F)F)=O.Cl>CCO.[OH-].[OH-].[Pd+2]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C@@H:10]([C@@H:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)[CH2:9][OH:8])=[C:13]([CH3:19])[CH:14]=1
Reactant: Cc1cc(Cl)ccc1O[C@@H](COCc1ccccc1)[C@H]1CCNC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)ccc1O[C@H](CO)[C@@H]1CCNC1

Procedure:
To a solution of (S)-3-[(R)-2-benzyloxy-1-(4-chloro-2-methylphenoxy)ethyl]-pyrrolidine.TFA (4.6 mg, 10 μmol) in EtOH (2.0 mL) at room temperature, was added concentrated HCl (˜50 μL). To the stirred mixture was added 20% Pd(OH)2/C (50 wt % water, 4.0 mg). The resulting mixture was degassed and flushed with hydrogen three times and then hydrogenated under a hydrogen balloon for 25 minutes. The mixture was filtered and the filtrate was concentrated. The resulting residue was redissolved in a mixture of AcOH (0.5 mL) and water (1.0 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, 98% purity). MS m/z: [M+H]+ calcd for C13H18ClNO2, 256.10. found 256.2.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH3:12][C:13](=O)[CH2:14][C:15](=O)[CH3:16]>C(O)(C)C>[CH3:12][C:13]1[CH:14]=[C:15]([CH3:16])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CC(C)O
Product: Cc1cc(C)n(-c2ccc(C(=O)O)cc2)n1
Yield: 99.8 %

Procedure:
4-Hydrazinylbenzoic acid (251a, 2 g, 13.2 mmol) and pentane-2,4-dione (1.35 mL, 13.2 mmol) were dissolved in isopropanol (40 mL) and refluxed for 15 hours. The solvent was removed under reduced pressure to afford 252a as a white solid (2.85 g, 99% yield). 1H NMR: (DMSO) δ 8.04 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 6.14 (s, 1H), 2.39 (s, 3H), 2.22 (s, 3H).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH3:55][C:56]([O:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)([CH3:58])[CH3:57]>CN(C)C(=O)C>[CH3:58][C:56]([O:59][CH:60]1[CH2:61][CH2:62][N:63]([C:4]([C:3]2[CH:7]=[C:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)[CH:9]=[CH:10][CH:2]=2)=[O:6])[CH2:64][CH2:65]1)([CH3:55])[CH3:57]
Reactant: CC(C)(C)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(C)(C)OC1CCN(C(=O)c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)CC1
Reaction time: 0.08 h

Procedure:
To 20 ml vial was added 3-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic acid (1b) (50 mg, 0.178 mmol). To this was added N,N-dimethylacetamide (2 mL) and triethylamine (70 μL, 0.445 mmol). This mixture was allowed to stir for 5 mins before addition of O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate, this solution was also allowed to stir for a further 5 minutes. A solution of 4-[(2-methylpropan-2-yl)oxy]piperidine hydrochloride (35 mg, 0.178 mmol) in N,N-dimethylacetamide (1 mL) and triethylamine (25 μl, 0.179 mmol) was then added and the reaction left to stir at ambient temperature for 2 hours before being purified by preparative HPLC to afford the desired compound; m/z (LC-MS, ESI+), RT=1.74 (M+H 420.4).
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:12]1[CH2:13][CH2:14][O:15][CH:11]1[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: OCCO
Reactant: O=Cc1nccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc2c(C3OCCO3)nccc2c1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A mixture of 1-isoquinolinecarboxaldehyde (7.2 g, 46 mmol), 5.7 g (92 mmol) of ethylene glycol, 200 ml of toluene and 2.3 g (12 mmol) of p-toluenesulfonic acid under argon in a 3 neck-flask equipped with a Dean-Stark Trap was refluxed for 6 h separating the water. The mixture was cooled to room temperature, and poured into an ice-cold 10% sodium carbonate solution. The aqueous layer was extracted with ether, the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 9.3 g of 1-(1,3-dioxolan-2-yl)isoquinoline.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[CH2:7]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCc1ccccc1)C1CCC(CO)CC1
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C1CCC(COCC(F)(F)F)CC1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 94.6 %

Procedure:
2,2,2-Trifluoro-ethanol (288 μL, 4.03 mmol) was added to a mixed solution of 4-hydroxymethyl-cyclohexanecarboxylic acid benzyl ester (100 mg, 0.403 mmol), 1,1′-azobis(N,N-dimethylformamide) (139 mg, 0.805 mmol) and tributyl-phosphine (199 μL, 0.805 mmol) in toluene (1.2 mL) at 0° C. The mixture was stirred at 65° C. for 1.5 hours and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-(2,2,2-trifluoro-ethoxymethyl)-cyclohexanecarboxylic acid benzyl ester as a colorless liquid (126 mg, 95%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[CH3:15])[CH3:2].N1C=CC=CC=1.[Br:22]Br>ClCCl>[Br:22][C:10]1[C:9]([CH3:14])=[C:8]([CH3:15])[C:7]([O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:12][C:11]=1[CH3:13]
Reactant: BrBr
Reactant: CCOCCOc1cc(C)cc(C)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOCCOc1cc(C)c(Br)c(C)c1C
Temperature: 0 °C
Yield: 102.4 %

Procedure:
To a mixture of 1-(2-ethoxyethoxy)-2,3,5-trimethylbenzene (1.0 g, 4.08 mmol), pyridine (0.097 mL, 1.20 mmol) and dichloromethane (10 mL) was added a solution of bromine (0.66 g, 4.12 mmol) in dichloromethane (1 mL) under stirring at 0° C., and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=49/1-hexane/ethyl acetate=4/1) to give the title compound (1.2 g, yield 99%) as a colorless oil.
Reaction SMILES: C[C@H:2]1[CH2:7][C@H:6]([C:8]([OH:10])=[O:9])[N:5](C([C@@H](NS(C2C3NCC(C)CC=3C=CC=2)(=O)=O)CCCN=C(N)N)=O)[CH2:4][CH2:3]1.O.N[CH2:38]CCCCCCCCCCC(OC)=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH2:6][C:8]([O:10][CH3:38])=[O:9]
Reactant: CC1CNc2c(cccc2S(=O)(=O)N[C@@H](CCCN=C(N)N)C(=O)N2CC[C@@H](C)C[C@@H]2C(=O)O)C1
Reactant: COC(=O)CCCCCCCCCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN
Reaction time: 16 h
Yield: 169.2 %

Procedure:
To a solution of argatroban monohydrate (300 mg, 0.570 mmol) and methyl 12-aminododecanoate (compound YS-004-17) (132 mg, 0.576 mmol) in anhydrous DMF (15 mL) was added HBTU (258 mg, 0.680 mmol). Stirring was continued at room temperature for 16 hours. The precipitates formed during the reaction were filtered off and DMF was removed by vacuum distillation. The residue was purified by preparative TLC using solvents CH2Cl2 /MeOH/NH3 (90/10/1, v/v) to give the titled compound (140 mg) (Yield: 28%). 1HNMR (MeOH-4, 300 MHz).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[S:22][CH2:23][C:24]([OH:26])=O.FC(F)(F)C([O-])=O.[NH2:34][C@@H:35]1[C:42](=[O:43])[N:41]2[C@@H:36]1[S:37][CH2:38][C:39](/[CH:47]=[C:48]1/[C:49](=[O:71])[N:50]([CH2:53][C:54]3[CH:59]=[CH:58][N+:57]([CH2:60][C:61](=[O:70])[NH:62][C:63]4[CH:68]=[CH:67][C:66]([OH:69])=[CH:65][CH:64]=4)=[CH:56][CH:55]=3)[CH2:51][CH2:52]/1)=[C:40]2[C:44]([OH:46])=[O:45]>CN(C)C(=O)C>[OH:69][C:66]1[CH:65]=[CH:64][C:63]([NH:62][C:61]([CH2:60][N+:57]2[CH:58]=[CH:59][C:54]([CH2:53][N:50]3[CH2:51][CH2:52]/[C:48](=[CH:47]\[C:39]4[CH2:38][S:37][C@H:36]5[N:41]([C:42](=[O:43])[C@H:35]5[NH:34][C:24](=[O:26])[CH2:23][S:22][C:14]5[S:13][C:17]6[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=6[N:15]=5)[C:40]=4[C:44]([O-:46])=[O:45])/[C:49]3=[O:71])=[CH:55][CH:56]=2)=[O:70])=[CH:68][CH:67]=1
Reactant: O=C(O)CSc1nc2ccccc2s1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)cc5)cc4)C3=O)CS[C@H]12
Agent: O=C([O-])C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)N(C)C
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CSc5nc6ccccc6s5)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)cc1

Procedure:
With 70.0 mg (0.43 mmol) 1,1′-carbonyldiimidazole, 96.0 mg (0.43 mmol) (benzothiazol-2-ylsulfanyl)-acetic acid and 233.8 mg (0.36 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml N,N-dimethylacetamide.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][CH:4]1[C:10]([OH:12])=[O:11].[CH:13]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:13][C:4]1([C:10]([OH:12])=[O:11])[CH2:5][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:3]1
Reactant: O=C(O)C1CC2(CCC2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)O)CC2(CCC2)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A slurry of 2.15 g (44.2 mmol) of sodium hydride (50% in oil) in 45.0 ml of dry THF was stirred under argon at -20° C. A solution of 5.52 g (40.0 mmol) of spiro[3.3]heptane-2-carboxylic acid in 5.0 ml of dry THF was added dropwise. The reaction mixture was stirred for 0.5 hr at -20° C. A solution of 44.5 mmol of freshly-prepared, -20° C lithium diisopropylamide in 31.0 ml of THF was added to the reaction mixture. The reaction mixture was stirred for 0.3 hr at 0° C. Methyl iodide (2.80 ml, 44.5 mmol) was added, and the reaction mixture stirred an additional 2.0 hr at 25° C. The reaction mixture was cooled to -20° C and the reaction quenched by careful addition of cold 10% aqueous HCl. The mixture was extracted with 1:1 ethylacetate-ether. The extracts were washed with brine, then dried (MgSO4), filtered, and solvents evaporated in vacuo. The residue was dissolved in 1 N NaOH and extacted three times with ether. The aqueous layer was acidified with 6 N HCl and extracted with 1:1 ethyl-acetate-ether. These extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to yield 5.1 g of 2-methylspiro[3.3]heptane-2-carboxylic acid as a light yellow oil (82.5%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.Cl[C:8]1[N:13]=[CH:12][C:11](/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])=[CH:10][CH:9]=1>>[C:18]1(/[C:15](/[CH2:16][CH3:17])=[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)\[C:11]2[CH:12]=[N:13][C:8]([O:6][C@H:3]3[CH2:4][CH2:5][NH:1][CH2:2]3)=[CH:9][CH:10]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O[C@H]1CCNC1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(O[C@H]2CCNC2)nc1)c1ccccc1
Yield: 75.6 %

Procedure:
Following the same procedure as described in example 3, (S)-pyrrolidin-3-ol (558 mg, 10 eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) to give the desired product (87 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), δ 7.54 (s, 1H), 7.20-7.23 (m, 2H), 7.10-7.16 (m, 4H), 7.00(d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.49 (d, J=8.4 Hz, 1H), 5.28 (bs, 1H), 3.15-3.32 (m, 2H), 2.94-3.05 (m, 2H), 2.43 (q, J=7.6 Hz, 1H) 1.90-2.10 (m, 1H), 1.79-1.89 (m, 1H), 0.86 (t, J=7.6 Hz, 3H); m/z=387 [M+1]+.