Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6].C(OCC)(=O)C.O.C(=O)(O)O>FC(F)(F)C(O)=O>[F:1][CH2:2][CH2:3][NH:4][C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]4)=[O:25])[CH:18]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc4c(ccn4C(=O)NCCF)c3)ccn2)CC1
Agent: O=C(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
After dissolving 160 mg of N1-(2-fluoroethyl)-5-[(2-{[(1-tert-butyloxycarbonyl-4-piperidyl)carbonyl]amino}-4-pyridyl)oxy]-1H-1-indolecarboxamide in 10 ml of trifluoroacetic acid, the solution was stirred at room temperature for 10 minutes. Ethyl acetate and bicarbonate water were added to alkalinity for liquid separation. The ethyl acetate layer was washed once with saline and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 86 mg of a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH3:14])[C@H:10]([C:15]([OH:17])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C@H]1C[CH2:23][NH:22][CH2:21][C@H]1C(O)=O.C(N(CC)CC)C.Cl.CNC.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH3:21][N:22]([CH3:23])[C:15]([C@H:10]1[C@@H:11]([CH3:14])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)=[O:17]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Reactant: C[C@H]1CCNC[C@H]1C(=O)O
Agent: CNC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N(C)C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of cis-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (prepared by N-Boc protection of cis-4-methylpiperidine-3-carboxylic acid, synthesized by the method described in Bulletin de la Societe Chimique de France 1986, 4, 663-8.) (0.4 g, 1.64 mmol) in tetrahydrofuran were added triethylamine (0.2 mL, 1.64 mmol), dimethylamine hydrochloride (132 mg, 1.64 mmol), and 1,1′-carbonyldiimidazole (CDI, 265 mg, 1.64 mmol). After 2 h, the mixture was quenched with water and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cis-tert-butyl 3-(dimethylcarbamoyl)-4-methylpiperidine-1-carboxylate (0.3 g, 68%) as a yellow solid. The material was used without further purification.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.Cl.N[CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2.C([N:37](CC)CC)C>C(O)C>[C:33]1([NH:37][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[C:34]2[CH2:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]=2[CH:30]=[CH:31][CH:32]=1
Reactant: NC1c2ccccc2-c2ccccc21
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(Nc4cccc5c4Cc4ccccc4-5)ncnc32)[C@H](O)[C@@H]1O
Yield: 63.1 %

Procedure:
4.0 g of 6-chloropurine riboside, 3.79 g of 9-aminofluorene hydrochloride and 3.52 g of triethylamine are refluxed in 100 ml ethanol under nitrogen for 20 hrs. the solvent is evaporated to dryness and residue is treated with 100 ml of cold water. Precipitated solid is filtered and treated with 50 ml of methanol-chloroform (1:1) affording 3.8 g (63%) of N6 -fluorenyladenosine having a m.p of 210°-212° C.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:17][C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)C(CC1CCCC1)c1cccc(Cl)c1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 61.9 %

Procedure:
A mixture of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid methyl ester (113 mg, 0.42 mmol) and 2-aminothiazole (84 mg, 0.84 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.4 mL, 1.69 mmol) was heated under reflux at 100° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (87 mg, 53%) as a white solid: mp 138.8–141.2° C.; EI-HRMS m/e calcd for C17H19ClN2OS (M+) 334.0906, found 334.0907.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1.[CH3:8][S:9]([OH:12])(=[O:11])=[O:10].[CH2:13]1[S:15][CH2:14]1>O>[CH3:8][S:9]([O-:12])(=[O:11])=[O:10].[CH3:1][N+:2]1([CH2:13][CH2:14][SH:15])[CH2:7][CH2:6][S:5][CH2:4][CH2:3]1
Reactant: CN1CCSCC1
Reactant: C1CS1
Reactant: CS(=O)(=O)O
Solvent: O
Product: CS(=O)(=O)[O-]
Product: C[N+]1(CCS)CCSCC1
Temperature: 65 °C
Yield: 86 %

Procedure:
To precooled (ice bath) N-methylthiomorpholine* (500 g, 42.7 mmol) was added methanesulfonic acid (1.47 mL, 20.5 mmol) and ethylene sulfide (1.30 mL, 21.4 mmol). The mixture was heated at 65° C. for 24 h and diluted with water (25 mL). The aqueous solution was washed with diethyl ether (3×25 mL), pumped under vacuum and poured over a silica gel reverse phase column; the title compound being eluted with water. The appropriate fractions were combined and evaporated to afford the thiol as an oil (4.80 g, yield 86%); ir (film) νmax : 2550 cm-1 (w,SH); 1Hmr (DMSO d6)δ: 3.25-2.95 (6H, m, CH2N⊕), 3.32 (3H, s, CH3N⊕), 3.20-2.65 (7H, m, CH2S, SH) and 2.32 ppm (3H, s, CH3SO3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N+:21]([CH3:24])([O-:23])=[O:22].C([O-])(=O)C.[NH4+]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:24]/[N+:21]([O-:23])=[O:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
To a mixture of 4-benzyloxy benzaldehyde (50 g, 0.24 mol) and acetic acid (200 mL) were added nitromethane (64 mL, 1.2 mol) and ammonium acetate (36 g, 0.47 mol), which was stirred for 90 minutes at 100° C. The reaction mixture was cooled to room temperature, and water (1 L) was added at the same temperature. The deposited solids were filtered to obtain the title compound (60 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:27].[Cl-].[NH4+]>C1COCC1>[Br:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCBr
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.82 mL) in THF (30 mL) was added n-butyllithium (2.5M in hexanes, 16.4 mL) at 0° C. and the mixture was stirred for 30 min at this temperature before being cooled to −78° C. Ethyl isobutyrate (5 mL) was added dropwise and the resultant mixture was stirred at −78° C. for 1 h before addition of 1,5-dibromopentane (5.61 mL). The reaction mixture was stirred at −78° C. for 1 h then at RT for 2.5 h before being poured into saturated ammonium chloride solution. The solution was extracted with ethyl acetate (×2), then the combined organics were washed with water and dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-25% ethyl acetate in cyclohexane to give the subtitled compound as a yellow liquid. Yield 4.45 g.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18]C)=[O:17])[C:3]1=[O:24].[OH-].[Na+]>CO.O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([OH:18])=[O:17])[C:3]1=[O:24]
Reactant: COC(=O)c1ccc(C)c(-c2cc3cnc(C)cc3n(C)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)O)ccc1C)c(=O)n2C

Procedure:
Methyl 3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoate 28 (3 g, 9 mmol) is suspended in a mixture of MeOH/water (1:1, mL) and treated with NaOH (2.2 g, 55 mmol) at 80° C. for 2 h. MeOH is removed in vacuo. The resultant mixture is acidified to pH=7, and the solid product is filtered and washed with water and dried overnight to yield 29. 1H NMR (400 MHz, DMSO-d6) δ 8.8 (s, 1H), 8.02 (s, 1H), 7.88 (dd, J=7.9, 1.8 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.44 (s, 1H), 7.42 (d, J=8 Hz, 1H), 3.65 (s, 3H), 2.62 (s, 3H), 2.23 (s, 3H). LC/MS (M+1, m/z): 309.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:3]=1.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)CC)C>C(O)CCC>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([N:30]3[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]3)[CH:3]=[C:4]([NH:18][CH:19]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:5]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: OC1CCNCC1
Reactant: COc1ccc(Nc2nc(Cl)cc(NC3CCCCCC3)n2)cc1Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2nc(NC3CCCCCC3)cc(N3CCC(O)CC3)n2)cc1Cl
Yield: 23 %

Procedure:
To a solution of compound 6-chloro-N2-(3-chloro-4-methoxy-phenyl)-N4-cycloheptyl-pyrimidine-2,4-diamine (0.15 g, 0.39 mmol) in 1-butanol (5 mL) was added 4-hydroxypiperidine (0.12 g, 1.18 mmol) at 25° C. with stirring. To this triethylamine (0.43 mL, 3.15 mmol) was added dropwise and the mixture was stirred at 25° C. for 30 minutes. This was heated and refluxed for 12 hours under nitrogen atmosphere. The mixture was concentrated under vacuum, diluted with cold water (30 mL) and extracted with ethyl acetate (2×30 mL). The organic layers were collected, combined, washed with brine (30 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum to give the desired compound. Yield: 23%.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[N:7][OH:8])=[CH:2]1.ClN1C(=O)CCC1=O.[NH4+].[Cl-].[CH3:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1>CN(C=O)C.ClCCl>[CH3:19][C:20]1[N:24]([C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][OH:8])[N:23]=[N:22][N:21]=1.[CH3:19][C:20]1[N:21]=[N:22][N:23]([C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][OH:8])[N:24]=1
Reactant: Cc1nnn[nH]1
Reactant: ON=Cc1ccsc1
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nnn(C(=NO)c2ccsc2)n1
Product: Cc1nnnn1C(=NO)c1ccsc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %
Yield: 13.7 %

Procedure:
To a solution of 3-thiophene carboxaldehyde oxime (8 g, 62.9 mmol) in DMF (80 ml) is added N-chlorosuccinimide (8.8 g, 66 mmol) portionwise, while maintaining the reaction temperature below 45° C. On complete addition, the mixture is stirred one hour at room temperature before being poured into a saturated aqueous NH4Cl solution. The mixture is extracted with ethyl acetate. The organic layer is washed successively with water and brine, dried (MgSO4), filtered and concentrated. The residue and 5-methyltetrazole (5.3 g, 62.9 mmol) are diluted in dichloromethane (80 ml) and treithylamine (11.4 ml, 82.1 mmol) is added dropwise at room temperature. After stirring overnight, a saturated aqueous NH4Cl solution is added. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed successively with water and brine, dried (MgSO4), filtered and concentrated. Silica-gel chromatography of the residue affords 5.5 g of 5-methyl-1-(3-thiophenecarbohydroximoyl)-tetrazole [yield 37.6%; 1H-NMR (DMSO-d6) δppm: 2.48 (s, 3H), 7.42 (d, 1H), 7.51 (d, 1H), 7.74 (dd, 1H), 12.7 (s, 1H)] and 2 g 5-methyl-2-(3-thiophenecarbohydroximoyl)-tetrazole [yield 13.7%; 1H-NMR (DMSO-d6) δppm: 2.62 (s, 3H), 7.40 (m, 2H), 7.73 (dd, 1H), 12.6 (s, 1H)].
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[CH3:15][N:16]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[C:17]([N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:20]1)=[O:18].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:15][N:16]([CH:30]1[CH2:35][CH2:34][N:33]([S:44]([CH3:43])(=[O:46])=[O:45])[CH2:32][CH2:31]1)[C:17]([N:19]1[CH:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[N:21]=[CH:20]1)=[O:18]
Reactant: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCNCC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)n1cnc(-c2cccnc2)c1)C1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To an ice-water cooled suspension of N-methyl-N-(piperidin-4-yl)-4-(pyridin-3-yl)-1H-imidazole-1-carboxamide bis(2,2,2-trifluoroacetate) (300 mg, 0.584 mmol) in dichloromethane (10 mL) was added DMAP (35.7 mg, 0.292 mmol), followed by the dropwise addition of triethylamine (0.326 mL, 2.337 mmol), followed in turn by addition of methanesulfonyl chloride (0.072 mL, 0.934 mmol). The solution was allowed to stir at room temperature overnight, whereupon it was quenched by the addition of methanol and allowed to stir at room temperature. The white precipitate was collected by filtration, washed with methanol and ether, then dried to give the product as a white solid, (158 mg, 74%).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:14][CH:15]=[CH2:16])[C:5]1=[O:6])[CH:2]=[CH2:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:22]=[CH:23][C:24](O)=O>>[CH2:14]([N:7]1[C:8](=[O:9])[C:10]2[NH:13][C:24](/[CH:23]=[CH:22]/[C:21]3[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:19]([O:18][CH3:17])[CH:20]=3)=[N:12][C:11]=2[N:4]([CH2:1][CH:2]=[CH2:3])[C:5]1=[O:6])[CH:15]=[CH2:16]
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Product: C=CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(OC)c3)nc2n(CC=C)c1=O

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 2.9 g (13.1 mmol) of 1,3-diallyl-5,6-diaminouracil and 2.99 g (14.4 mmol) of 3,4-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 2.80 g (yield of Compound 69 as pale yellow flocculent precipitates.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=1.[NH2:16][C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([O:27][CH2:28][CH2:29][OH:30])[CH2:18]1.O.C(OCC)(=O)C>O1CCCC1>[Cl:11][C:6]1[N:5]=[C:4]([S:12][CH2:13][CH2:14][CH3:15])[N:3]=[C:2]([NH:16][C@H:17]2[C@@H:21]3[O:22][C:23]([CH3:25])([CH3:26])[O:24][C@@H:20]3[C@@H:19]([O:27][CH2:28][CH2:29][OH:30])[CH2:18]2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Reactant: CCCSc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCSc1nc(Cl)c([N+](=O)[O-])c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Yield: 44.7 %

Procedure:
A solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (1.07 g, 3.99 mmol, 1.00 equiv.), and 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)ethanol (570 mg, 4.41 mmol, 1.20 equiv.) in tetrahydrofuran (20 mL) was stirred at 0-10° C. for about 2 hours and then water (20 mL) was added. Standard extractive workup with ethyl acetate (3×20 mL) afforded the title product as a yellow oil (800 mg; yield=45%). 1H NMR (300 MHz, CDCl3) δ: 8.65 (b, 1H), 4.66-4.76 (m, 2H), 4.56 (m, 1H), 3.99 (d, J=7.5 Hz, 1H), 3.70-3.87 (m, 3H), 3.64-3.67 (m, 1H), 3.07-3.20 (m, 2H), 2.34 (m, 1H), 1.97 (m, 1H), 1.76-1.82 (m, 2H), 1.46 (s, 3H), 1.27 (s, 3H), 1.07 (t, J=7.5 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[OH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:15][O:14][CH2:13][CH2:12][O:11][C:4]1[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=[C:2]([O:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1
Reactant: Oc1cccnc1
Reactant: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Oc2cccnc2)cnc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 20 %

Procedure:
5-Chloro-3-(2-methoxy-ethoxy)-2-nitro-pyridine (2.6 mmol) is dissolved in DMF (12 ml), 3-hydroxypyridine (3 eq.) and K2CO3 (4 eq.) is added. The reaction is heated to 120° C. in the microwave for 45 min. The solvent is removed in vacuo and dissolved in water (200 ml) and extracted with methyl-tert.-butyl ether. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-(2-Methoxy-ethoxy)-2-nitro-5-(pyridine-3-yloxy)-pyridine is obtained after column chromatography (heptane/ethyl acetate) as yellow oil in a yield of 20%. HPLC (method C): 1.23 min; LC-MS (method A): 1.18 min, 292.15 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:23]([O:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:24])[CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)n1ccnc1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.6 %

Procedure:
2-(4-bromophenyl)imidazole (5.3 g, 23.76 mmol) was taken into THF (100 mL) followed by addition of DIPEA (5 mL, 28.5 mmol) and isobutyl chloroformate (3.4 mL, 26.1 mmol) and the resulting solution was stirred for 30 minutes at room temperature. The solution was then concentrated and the residue partitioned with ethyl acetate and water. The organic phase was washed once with 10% aqueous citric acid, brine then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5:1 hexanes:ethyl acetate) to give isobutyl 2-(4-bromophenyl)-1H-imidazole-1-carboxylate (3.5 g, 46% yield) as an amorphous residue.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[O:40]CC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:36])[CH:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16][CH:17]=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=CCC(Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Yield: 48 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[2-(4-benzyloxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (0.96 g, 1.8 mmol), THF (21 mL) and water (7 mL) with 2.5% osmium tetroxide in t-butanol (46 mg, 0.18 mmol). Add sodium periodate (1.17 g, 5.5 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 0.46 g (48%) of desired product. MS (m/z): 526 (M+).
Reaction SMILES: [Mg].[CH:2](Cl)([CH3:4])[CH3:3].C1([CH2:12][SiH:13](Cl)[Cl:14])C=CC=CC=1.O1CCCC1.[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:12][Si:13]([C:23]1[CH:22]=[CH:21][CH:26]=[CH:25][CH:24]=1)([CH:2]([CH3:4])[CH3:3])[Cl:14]
Reactant: Cl[SiH](Cl)Cc1ccccc1
Reactant: CCCCCC
Reactant: CC(C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)[Si](C)(Cl)c1ccccc1
Temperature: 25 °C

Procedure:
36 g (1.5 mol) magnesium was introduced into a 2 L four-neck flask equipped with a reflux condenser, stirring rod, thermometer, and addition funnel, and was dried under nitrogen. 800 mL dry tetrahydrofuran (THF) was then added. A Grignard reagent was prepared by slowly dripping in 117.8 g (1.5 mol) isopropyl chloride from the addition funnel. Then, 267.6 g (1.4 mol) phenylmethyldichlorosilane was dripped in from the addition funnel. After completion of this addition, the reaction was brought to completion by continuing to stir for 5 hours at the reflux temperature of THF. After cooling to room temperature, 500 mL hexane was added, the reaction mixture was filtered, and the solvent was distilled from the filtrate. Continuing with distillation in vacuo afforded 258 g (1.3 mol) of the target methylphenylisopropylchlorosilane (bp=85 degrees Centigrade/7 mmHg).
Reaction SMILES: [C:1]([OH:10])(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]=1.Cl>C(O)C>[O:10]=[C:1]1[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][N:13]12
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CCO
Product: O=C(O)c1ccc2nc3ccccc3c(=O)n2c1
Yield: 44.5 %

Procedure:
A reaction mixture containing 4.35g (31.8 mmol) of anthranilic acid, 5.00g (31.8 mmol) of 6-chloronicotinic acid, 3ml of conc. HCl and 80ml of ethanol was heated at reflux for 21 hours. The mixture was cooled and filtered to give 3.40g (38.9%) of the expected product, mp. 323°-325° dec. The analytical sample was obtained by recrystallization from methanol-ether, mp. 323°-325° dec.
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH:3]([C:10](Cl)=[O:11])[CH:2]2[CH3:13].[NH3:14]>>[CH:1]12[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH:3]([C:10]([NH2:14])=[O:11])[CH:2]2[CH3:13]
Reactant: CC1C(C(=O)Cl)CC2CC1C2(C)C
Reactant: N
Product: CC1C(C(N)=O)CC2CC1C2(C)C

Procedure:
2g of (+)-pinane-3-carboxylic acid chloride are mixed with concentrated aqueous ammonia solution; the corresponding carboxylic acid amide precipitates and is filtered off and dried. It melts at 131° C and has an optical rotation of [α]D24 = +22.4° (c = 1, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([N:23]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[CH:6][C:7]=1[F:8].O.NN>C1COCC1.CO>[NH2:23][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(c1ccc(F)c(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CC(N)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.2 %

Procedure:
To a solution of 303 (0.0507 g, 0.1072 mmol) and THF/MeOH (1:1) was added hydrazine monohydrate (0.080 mL, 1.072 mmol) and the reaction stirred at RT 3 d. A thick white precipitate formed which was filtered through CELITE. The solution was concentrated and purified by SiO2 chromatography to afford 0.0214 g (58%) of (2R)-tert-butyl 2-(2-amino-2-(3-chloro-4-fluorophenyl)ethyl)pyrrolidine-1-carboxylate (305) as a clear oil.