Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:19][N:20]1[CH:24]=[CH:23][C:22]([NH2:25])=[N:21]1>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH3:18][S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH:25][C:22]3[CH:23]=[CH:24][N:20]([CH3:19])[N:21]=3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(Br)nc2)cc1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: C1COCCO1
Product: Cn1ccc(Nc2ccc(Oc3ccc(S(C)(=O)=O)cc3)cn2)n1
Temperature: 80 °C
Yield: 55 %

Procedure:
2-Bromo-5-(4-methanesulfonyl-phenoxy)-pyridine (0.47 mmol), sodium-tert.-butylate (1.4 eq.), and 1-methyl-1H-pyrazole-3-amine (1.2 eq.) are dissolved in degassed dioxane (2.5 ml) and heated to 80° C. Chloro(di-2-norbornylphosphino)(2-dimethylaminoferrocene-1-yl)palladium (II) (5.9 mg) in degassed dioxane (1 ml) is added and the reaction mixture is heated for 1 hour at 142° C. in the microwave. The reaction is quenched with ethylacetate (30 ml) and filtrated over celite. The solvent of the filtrate is removed in vacuo [5-(4-Methanesulfonyl-phenoxy)-pyridine-2-yl]-(1-methyl-1H-pyrazole-3-yl)-amine (“A27”) is obtained after reversed phase column chromatography (water/acetonitrile+0.1% TFA) as orange powder in a yield of 55%; HPLC (method C): 1.57 min; LC-MS (method A): 0.787 min, 345.15 (M+H+);
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=CC=1.[C:8]([O:11][CH2:12][CH3:13])(=[O:10])[CH3:9].[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:8]([O:11][CH2:12][C:13]1[CH:5]=[CH:6][CH:1]=[CH:7][C:15]=1[C:14]([OH:17])=[O:16])(=[O:10])[C:9]1[CH:4]=[CH:5][CH:6]=[CH:1][CH:7]=1
Reactant: Cc1ccccc1
Reactant: CC(=O)O
Reactant: CCOC(C)=O
Product: O=C(OCc1ccccc1C(=O)O)c1ccccc1

Procedure:
TLC: toluene:ethyl acetate: acetic acid, 5:5:0.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]#[N:23]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([O:8][CH:9]([C:11]#[N:12])[CH3:10])=[CH:6][CH:7]=1)[O:13][CH2:21][C:22]#[N:23]
Reactant: CC(C#N)Oc1ccc(Cl)cc1O
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C#N)Oc1ccc(Cl)cc1OCC#N
Reaction time: 3.5 h

Procedure:
A mixture of 3-chloro-6-(1-cyanoethoxy)-phenol (34.6 g., 0.175 mole), finely powdered anhydrous potassium carbonate (37.2 g., 0.27 mole) and acetone (250 ml.) is stirred under reflux while chloroacetonitrile (9.8 g., 0.13 mole) is added over a period of about 5 minutes. The mixture then is heated under reflux with vigorous stirring for 1.5 hours, whereupon more potassium carbonate (12.5 g., 0.09 mole) and chloroacetonitrile (3.4 g., 0.045 mole) are added. Stirring and heating are continued for 3.5 hours, then the mixture is filtered and the filter-cake washed with acetone. Evaporation of the combined filtrate affords 3-chloro-6-(1-cyanoethoxy)-phenoxyacetonitrile which is recrystallized from aqueous alcohol.
Reaction SMILES: [NH2:1][S:2][O:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29]CC)=O)=[N:12]2)=[CH:7][CH:6]=1.[OH-].[NH4+:33]>CO>[NH2:1][S:2][O:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([NH2:33])=[O:29])=[N:12]2)=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Agent: [OH-]
Solvent: CO
Product: NSOOc1ccc(-n2nc(C(N)=O)c3c2-c2cc([N+](=O)[O-])ccc2CC3)cc1
Yield: 68 %

Procedure:
The material of Example 2 (718 mg, 0.0016 mol), conc. ammonium hydroxide (30 mL), and methanol (15 mL) were stirred in a stoppered flask for 72 hours. Contents were filtered to give a light amber solid (606 mg). The solid was recrystallized from acetonitrile to give the product as a light amber solid, 450 mg (68% yield). FABHRMS m/z 414.0902 (M+H, C18H16N5O5S requires 414.0872). 1H NMR (DMSO-d6/300 MHz) 8.15-7.95 (m, 3H); 7.83 (d, 2H); 7.80-7.40 (m, 6H); 3.20-2.95 (m, 4H). Anal. Calcd for C18H15N5O5S: C, 52.30; H, 3.66; N, 16.94. Found: C, 52.04; H, 3.64; N, 16.61.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[NH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:3][CH:2]=1
Reactant: NCc1ccncc1
Reactant: O=Cc1ccncc1
Product: c1cc(CNCc2ccncc2)ccn1

Procedure:
In this Example, reductive amination of 4-pyridine-carboxaldehyde (2) with 4-(aminomethyl)pyridine (1) was carried out using a one-pot two-step protocol to produce bis((pyridin-4-yl)methyl)amine (4). Time-resolved mass spectra of the aldehyde-amine condensation step and the imine reduction step are shown in FIG. 16. Ions were identified according to their m/z values and confirmed by tandem mass experiment. Reactant 1 was first injected into the methanol reaction solvent. Ions of protonated 1 at m/z 109 were detected at 0.4 min later, on the heels of which the protonated dimer at m/z 217 appeared and reached its steady state within 4.8 s. (FIG. 16 panels A-B) After reactant 2 was injected into the reaction solution and the protonated methanol adduct ions of the monomer and dimer of 2 at m/z 140 and 279 showed up. The ions of the intermediate (pyridin-4-yl)-N-((pyridin-4-yl)methylene)methanamine (3) at m/z 198 and 230 formed quickly and the intensity increased sharply (FIG. 16 panel C). The intensity of ions of 1 decreased but the ions did not disappear, which corresponded to the fact that this is an equilibrium reaction (FIG. 16 panel D). About 50 min later, sodium borohydride solution was injected into the system. The sodiated adduct ions of product 4 at m/z 222 started to appear, while the intermediate ions of 3 decreased a lot (FIG. 16 panel E). Ten minutes later, the peak of the product 4 was reaching its highest intensity (FIG. 16 panel F). The selected ion chronogram shows dynamic changing of ions corresponding to the precursor 1, intermediate 3 and product 4 (FIG. 17). The kinetic process of reductive amination can be clearly seen. The first condensation step of this reaction happened very fast; once 2 was added to the solution of 1, it took less than 1 min for the reaction to reach equilibrium. The intermediate 3 was generated simultaneously with the decrease of 1. The second reduction step was not as fast as the first step. With the reduction of intermediate 3, the first step was driven to the right. Thus ions of 1 were depleted. Altogether, it took around 10 min for the product 4 to reach its highest intensity. The total monitoring time was 90 min without any clogging in the fused-silica capillary using high concentrations of reaction solution that are representative of those of industrial interest.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH:2]=C.I([O-])(=O)(=O)=[O:26].[Na+].N1C(C)=CC=CC=1C>O.O1CCOCC1.[Os](=O)(=O)(=O)=O>[O:14]=[C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[CH:4]([CH2:1][CH:2]=[O:26])[CH2:13]1
Reactant: C=CCC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: O=CCC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h

Procedure:
Osmium tetroxide (5% in water, 2.0 mL, 0.33 mmol, 0.025 equiv) was added to a biphasic mixture of benzyl 2-allyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1A) (4.20 g, 13.1 mmol, 1 equiv), sodium periodate (11.2 g, 52.3 mmol, 4.00 equiv) and 2,6-lutidine (3.04 mL, 26.1 mmol, 2.0 equiv) in water (33 mL) and dioxane (98 mL) at 23° C. The reaction mixture was stirred at 23° C. for 3 h, and then it was partitioned between water and dichloromethane. The aqueous layer was further extracted with dichloromethane (1×), and the combined organic layers were dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (15% ethyl acetate-hexanes, grading to 70% ethyl acetate-hexanes) to afford 25A. [M+H]+: 324.1
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH2:35]O)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1>CN(C)C=O.C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:7]=[C:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:14]([O:16][CH2:35][C:27]2[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=[C:25]([C:24]([F:23])([F:37])[F:38])[CH:26]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1CCC(C(=O)OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
Oxalyl chloride (4.8 mL, 55 mmol) was added to a solution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2, 6 g, 27 mmol) and dimethylformamide (1 drop) in toluene (150 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and toluene was added. The solvent was evaporated under reduced pressure and the residue was dissolved in toluene (100 mL). 3,5-Bis(trifluoromethyl)benzenemethanol (6.25 g, 26 mmol) and 4-dimethylaminopyridine (3.62 g, 30 mmol) were added and the mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and hydrochloric acid (2M, 100 mL). The organic layer was dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/CH2Cl2 (60:40 increasing to 50:50) to give the title compound (4.5 g, 40%). 1H NMR (360 MHz, CDCl3) δ 2.33-2.53 (6H, m), 2.72-2.77 (2H, m), 5.23 (2H, s), 7.28-7.41 (5H, m), 7.51 (2H, s), and 7.77 (1H, s).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][Si@H:7]([CH2:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15])[CH2:6][CH2:5]1.[Mg].BrC1C=CC([C:24]2[C:25]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)=[CH:26][CH:27]=[CH:28][CH:29]=2)=CC=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[CH2:10]([Si@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][C:24]2[CH:25]=[CH:26][C:27]([C:28]3[CH:29]=[CH:24][C:25]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=4)=[CH:26][CH:27]=3)=[CH:28][CH:29]=2)[CH2:5][CH2:6]1)[CH2:11][CH:12]=[CH:13][CH2:14][CH3:15]
Reactant: CCC=CCC[Si@H]1CC[C@H](CCCl)CC1
Reactant: Fc1ccc(-c2ccccc2-c2ccc(Br)cc2)cc1F
Agent: [Pd]
Agent: [Mg]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC=CCC[Si@H]1CC[C@H](CCc2ccc(-c3ccc(-c4ccc(F)c(F)c4)cc3)cc2)CC1

Procedure:
24.5 g (100 mmol) of trans-1-(2-chloroethyl)-4-(3-hexenyl)-4-silacyclohexane was dripped into a mixture of 2.4 g of magnesium (100 mmol) and 60 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 300 ml THF solution of 34.5 g of 4-bromo-3",4"-difluoroterphenyl and a catalytic amount of tetrakis (triphenylphosphine) palladium (0). After a conventional after treatment, the reaction mixture thus obtained was purified by means of chromatography to obtain 39.6 g (yield 87%) of the target product.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6]#[CH:7])(=[O:3])[CH3:2].[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14].C=O.O1CCOC[CH2:21]1>CCOCC>[CH2:13]([N:15]([CH2:16][CH3:17])[CH2:21][C:7]#[C:6][C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:14]
Reactant: C#C[C@H](CCCCC)OC(C)=O
Reactant: C1COCCO1
Reactant: CCNCC
Agent: C=O
Solvent: CCOCC
Product: CCCCC[C@@H](C#CCN(CC)CC)OC(C)=O
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 3(S)-acetyloxy-1-octyne (58.5 g., 0.35 mole), diethylamine (28.5 g., 0.39 mole), paraformaldehyde (13.8 g., 0.46 mole), and p-dioxane (60 ml.) is heated on the steam bath for 17 hours, then cooled to room temperature and diluted with ether (250 ml.). The resulting solution is extracted with 5% hydrochloric acid (300 ml.) providing an aqueous extract (acidic) which is made basic with 10% sodium hydroxide solution and extracted with ether. The organic extract is dried over sodium sulfate and filtered. In vacuo evaporation of the filtrate leaves a residual oil which is distilled to provide the title compound (73.1 g., 89%), b.p. 103°-109° C./0.3 mm.; [α]D26 -80° (C 3.3, CHCl3).
Reaction SMILES: [NH2:1][CH:2]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]([NH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:30]1([CH2:36][C:37](Cl)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl>[C:24]1([CH:2]([NH:1][C:37](=[O:38])[CH2:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][CH:15]=2)=[O:12])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC(c1ccccc1)C(NC(=O)Nc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.1 %

Procedure:
To a solution of [R-(R*,R*)] and [S-(R*,R*)]-N-(2-amino-1,2-diphenylethyl)-N'-[4-(trifluoromethyl)phenyl]urea (0.1 g, 0.25 mmol) in dichloromethane (5 mL) is added phenylacetyl chloride (0.05 g, 0.3 mmol) followed by triethylamine (0.03 g, 0.3 mmol) in one portion. The resulting mixture is stirred 2 hours at room temperature before concentrating in vacuo. The residue is dissolved in diethyl ether and the organic layer washed with aqueous 1N NaOH, aqueous saturated NaCl, and dried over MgSO4. Filtration and concentration gives an oil which is purified by flash chromatography (SiO2, EtOAc/hexane eluent). The resulting solid is recrystallized from ethyl acetate/hexane to give 0.07 g (52%) of desired white solid, mp 233.5°-234° C. NMR (DMSO-d6): 3.46 (dd, 2H, J=26.4, 14 Hz), 5.10 (m, 2H), 6.97-7.19 (m, 20H), 7.57 (s, 4H), 8.82 (d, 1H, J=8.3 Hz), 8.98 (s, 1H). Analysis calculated for C30H26F3N3O2.0.71H2O: C, 67.94; H, 5.21; N, 7.92. Found: C, 67.94; H, 4.84; N, 7.86.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].[OH:5][N:6]=[C:7]([NH2:20])[CH2:8][C:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[Cl:19].N1C=CC=CC=1>C(Cl)Cl>[Cl:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:18][C:9]=1[CH2:8][C:7]1[NH:20][S:1](=[O:2])[O:5][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: NC(CC1=C(Cl)c2ccccc2CC1)=NO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S1NC(CC2=C(Cl)c3ccccc3CC2)=NO1
Yield: 31.8 %

Procedure:
Thionyl chloride (0.55 mL, 7.5 mmol) was added dropwise to a mixture of N'-hydroxy-(1-chloro-3,4-dihydro-2-naphthalenyl)ethanimidamide (1.6 g, 6.8 mmol) and pyridine (1.10 mL, 13.6 mmol) in dry CH2Cl2 (25 mL) at 0° C. After the addition, the reaction was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ether (3×50 mL). The organics were washed with brine, dried (MgSO4), and concentrated to obtain a black froth. The froth was chromatographed on silica gel (twice: eluant 4% MeOH/CH3Cl2 and eluant 2% MeOH/CH2Cl2) to yield 612 mg (32%) of an off-white solid, m.p. 90.5°-91.5° C.
Reaction SMILES: [NH:1]([C:8](OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[CH3:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH:32]=O.[F:34][C:35]([F:47])([F:46])[S:36]([C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>>[F:34][C:35]([F:47])([F:46])[C:5]([OH:7])=[O:6].[CH3:5][C@@H:2]1[N:1]([CH2:32][C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH3:25])[C:8](=[O:9])[N:43]([C:42]2[CH:44]=[CH:45][C:39]([S:36]([C:35]([F:46])([F:34])[F:47])(=[O:37])=[O:38])=[CH:40][CH:41]=2)[C:3]1=[O:4]
Reactant: Cc1cnccc1C=O
Reactant: O=C(N[C@@H](CO)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Product: Cc1cnccc1CN1C(=O)N(c2ccc(S(=O)(=O)C(F)(F)F)cc2)C(=O)[C@@H]1C
Product: O=C(O)C(F)(F)F

Procedure:
The compound is prepared from 0.04 mmol of resin, 0.12 mmol of N-Fmoc-L-Ala(OH), 0.20 mmol of 3-methyl-4-pyridinecarboxaldehyde, and 0.10 mmol of 4-(trifluoromethanesulfonyl)aniline, in the same way as in Example 1. After purification by preparative LC-MS, 16 mg of expected product are obtained.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][S:6][C:5](=[O:8])[NH:4]1.[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:1][CH2:2][C@H:3]1[CH2:7][S:6][C:5](=[O:8])[NH:4]1
Reactant: C1=COCCC1
Reactant: O=C1N[C@@H](CO)CS1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1N[C@@H](COC2CCCCO2)CS1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-3 (3.3 g, 25 mmol) and 20 mg of p-toluenesulfonic acid in CH2Cl2 (100 mL) was added 3,4-dihydro-2H-pyran (2.7 mL, 30 mmol) and the resulting solution was stirred at rt for 30 minutes. Triethylamine (0.1 mL) was added and the solution was concentrated in vacuo. The compound was purified by flash chromatography using 40% EtOAc/hexanes to yield 4 g of 3-4 as a colorless oil. 1H NMR (400 MHz, acetone-d6): δ 7.0 (br s, 1H), 4.6 (s, 1H), 4.0 (m, 1H), 3.8 (m, 2H), 3.6 (m, 3H), 3.3 (dd, 1H), 1.9–1.4 (m, 6H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[CH:24]([CH2:28][OH:29])[NH:23][CH:22]=[N:21][C:20]1=2)(=[O:3])[CH3:2].[H-].[Na+].[S:32](Cl)([CH3:35])(=[O:34])=[O:33].O.C(Cl)(Cl)Cl>C(COC)OC>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[CH:27]=[N:26][C:25]2[CH:24]([CH2:28][O:29][S:32]([CH3:35])(=[O:34])=[O:33])[NH:23][CH:22]=[N:21][C:20]1=2)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c2N=CNC3CO)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c2N=CNC3COS(C)(=O)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 17 h
Yield: 91 %

Procedure:
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-6-hydroxymethyl-1,6-dihydropurine (VI) (217 mg.) obtained in (2) was dissolved in purified anhydrous dimethoxyethane (10 ml.) and cooled to -10° to -15° C. To the cooled solution were added sodium hydride (76 mg., 3 moles) and mesyl chloride (180 mg., 3 moles), successively. The reaction was conducted at 0° - 5° C. for 17 hours. The reaction mixture was then treated with water-chloroform and the chloroform layer thus separated was washed with 0.5% aqueous sodium hydrogen carbonate, then with water, dried over anhydrous sodium sulfate and concentrated to yield II as a pale-yellow oil (235 mg., yield: 91%). This substance is unstable and decomposes in chloroform within 2-3 hours.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3cccc(F)c3)noc2N)CC1
Yield: 65.8 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (482 mg, 1.21 mmol, 66%) was obtained.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[C:5]1([N:11]=[C:12]=[S:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.Br[CH2:21][C:22](OC)=[O:23].Cl>CO>[C:5]1([N:11]2[C:22](=[O:23])[CH2:21][S:13]/[C:12]/2=[N:4]\[CH:1]([CH3:3])[CH3:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: CC(C)N
Reactant: COC(=O)CBr
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)/N=C1\SCC(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of isopropylamine (1.31 g, 22.19 mmol) in methanol (25 mL) is added portionwise phenylisothiocyanate (3.0 g, 22.19 mmol). The solution which becomes slightly warm during the addition is stirred at rt for 4 h before pyridine (2.63 g, 33.29 mmol) and methyl bromoacetate (3.39 g, 22.19 mmol) is added. The mixture is stirred for another 16 h at rt before it is poured onto 1 N aq. HCl (100 mL) and extracted with diethyl ether (150 mL). The aq. layer is neutralised by adding sat. aq. NaHCO3 and extracted with diethyl ether (4×150 mL). The organic extracts are dried over MgSO4 and evaporated. The remaining solid is suspended in diethyl ether/heptane, filtered off, washed with additional diethyl ether/heptane and dried to give 3-phenyl-2-[(Z)-isopropylimino]-thiazolidin-4-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36](CP(=O)(OCC)OCC)=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3C=2C[N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC([CH2:66][CH2:67][CH2:68][CH2:69][PH:70](=[O:74])[O:71][CH2:72][CH3:73])=CC=2OC)N=1.[NH2:79]C1C=CC(C2C=NN(CCCO)C=2)=C2C=1C(=O)N(C)C2.NC1C(C(OCC)=O)=NC=CC=1>>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[N:79]=[C:14]([C:15](=[O:20])[NH:16][CH3:19])[C:13]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:66][CH2:67][CH2:68][CH2:69][PH:70](=[O:74])[O:71][CH2:72][CH3:73])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[CH:12][CH:11]=2)[CH:7]=[N:6]1
Reactant: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1
Reactant: CN1Cc2c(-c3cnn(CCCO)c3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOC(=O)c1ncccc1N
Product: CCO[PH](=O)CCCCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(OC)c1

Procedure:
Prepared analogously to Compound 1B replacing Compound 1E with ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propylphosphinate (Compound 37C, 0.680 g, 1.50 mmol) and Compound 1C with Compound 6F (0.420 g, 1.52 mmol) to isolate the title compound as 650 mg of a light yellow solid (63%). MS (ESI): m/z 691.25 [M+H]+. UPLC: tR=0.98 min (polar—2 min).