Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].ON1C2C=CC=CC=2N=N1.[CH2:38](N)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[C@@H:2]([C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:6][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: NCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(CC[C@@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)NCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 11.4 grams of Z-D-Gln-OBzl and 4.15 grams of 1-hydroxybenzotriazole in 50 ml of absolute tetrahydrofurane are added 3.35 ml of benzylamine and 6.76 grams of DCC. The mixture is stirred for 1 hour at 0° C and 1 hour at room temperature, the precipitate is filtered off with suction and the filtrate is concentrated. The residue is triturated in succession with NaHCO3 solution, 2n-HCl NaHCO3 solution and water, filtered off with suction and washed with water. Yield: 16.2 grams, melting point 144°. For purification recrystallisation from isopropanol is carried out. The product is washed with petroleum ether. Yield: 6 grams, melting point 149°, [α]D20 = -0.1 (c = 1, in glacial acetic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: COc1cccc(CN)c1
Solvent: COCCOC
Product: COc1cccc(CNc2nc(N)nc(-c3ccco3)c2C#N)c1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-methoxybenzylamine in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:10][CH2:11][C:12](O)=[O:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]1([CH2:7][CH2:8][O:9][C:12](=[O:13])[CH2:11][SH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CS
Reactant: OCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CS)OCCc1ccccc1

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser, hot plate (with magnetic stirring apparatus included within) and spin bar are placed 12.2 grams of phenylethyl alcohol; 23.0 grams mercaptoacetic acid; and 0.5 grams of para-toluene sulphonic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[O:5][CH2:6][CH2:7][CH2:8][N:9]=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[O:5][CH2:6][CH2:7][CH2:8][NH2:9]
Reactant: [H][H]
Reactant: Cc1ccc(OCCCN=[N+]=[N-])cc1C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(OCCCN)cc1C
Yield: 47.8 %

Procedure:
6.20 g (30.2 mmol) of 3-(3,4-dimethylphenoxy)propylazide obtained in step 2 was dissolved in 150 ml of ethyl acetate and then 4.99 g of 5% Pd/C was added thereto to carry out a hydrogenation reaction at a hydrogen pressure of 40 psi for 30 minutes. The reaction mixture was passed through a Celite™ layer to remove Pd/C, concentrated under a reduced pressure to produce a residue, which was distilled under a reduced pressure to obtain 2.59 g (yield 48%) of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:16]([O-])=O)[CH:5]=1)[CH3:2].[H][H]>CO.[Pd]>[NH2:16][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]([O:14][CH3:15])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(N)c(C(=O)OC)cc1OC
Yield: 92.5 %

Procedure:
A mixture of methyl 4-ethoxy-5-methoxy-2-nitrobenzoate (8.38 g, 32.8 mmol) and Pd/C (10%, 0.85 g) in MeOH (20 mL) was stirred under 1 atmosphere of hydrogen at room temperature for 6 hours. The reaction mixture was filtered with Celite and washed with MeOH. The filtration was concentrated under reduced pressure to give methyl 2-amino-4-ethoxy-5-methoxybenzoate as solid (6.832 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.30 (s, 1H), 6.13 (s, 1H), 5.56 (br, 2H), 4.08 (q, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 1.48 (t, 3H); LC-MS (ESI) m/z 226 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[N:4]=[C:3]([CH2:10][O:11][CH2:12][O:13][CH3:14])[C:2]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:7][CH:6]=1
Reactant: C1CCNC1
Reactant: COCOCc1nc(OC)ccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCOCc1nc(OC)ccc1N1CCCC1
Yield: 13.6 %

Procedure:
A solution of 3-bromo-6-methoxy-2-(methoxymethyloxy)methylpyridine (324.6 mg, 1.24 mmol), tris(dibenzylideneacetone)(chloroform)dipalladium(0) (32.7 mg, 0.03 mmol), (2-biphenyl)di-t-butylphosphine (18.5 mg, 0.06 mmol), sodium t-butoxide (357 mg, 3.71 mmol) and pyrrolidine (640 mg, 3.74 mmol) in toluene (4.5 mL) was stirred at 135° C. for 3 hours in a sealed tube. The reaction mixture was extracted with chloroform/water, and the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative silica gel thin layer chromatography (hexane:ethyl acetate=3:1) to obtain 6-methoxy-2-(methoxymethyloxy)methyl-3-(pyrrolidin-1-yl)pyridine (42.7 mg, 14%) as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([OH:22])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1)[CH3:2].C[O:24][C:25](=[O:48])[C@H:26]([C@@H:45]([CH3:47])O)[NH:27]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2([O:22][C@H:45]([CH3:47])[C@@H:26]([C:25]([OH:48])=[O:24])[NH2:27])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]3[C:21]2=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: CCc1cccc(C2(O)c3ccccc3-c3ccccc32)c1
Product: CCc1cccc(C2(O[C@H](C)[C@H](N)C(=O)O)c3ccccc3-c3ccccc32)c1

Procedure:
from 9-(3-ethylphenyl)-9H-fluoren-9-ol (Example 3r) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester;
Reaction SMILES: [N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH:23]=[CH2:24])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1>CO.[Pd]>[N:1]1[C:9]([NH:10][C@H:11]([C:13]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:15](=[O:25])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][CH3:24])[CH3:12])=[C:8]2[C:4]([NH:5][CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: C=Cc1cccc2cc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: [Pd]
Solvent: CO
Product: CCc1cccc2cc([C@H](C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-2-phenyl-8-vinylisoquinolin-1(2H)-one (8) (120 mg, 0.29 mmol) and palladium (10% weight on carbon, 24 mg) in anhydrous MeOH (25 mL) was degassed and flushed with hydrogen (three cycles). The reaction mixture was stirred under a hydrogen atmosphere (hydrogen balloon) at RT for 1 h. The mixture was filtered through Celite and rinsed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-ethyl-2-phenylisoquinolin-1(2H)-one (9). ESI-MS m/z: 411.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)([CH3:19])[C:14]([O:16]CC)=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.O>C1COCC1>[CH:1]1([C:4]2[C:5]([O:26][CH2:27][C:28]([F:29])([F:30])[F:31])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)([CH3:19])[C:14]([OH:16])=[O:15])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(C)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(C)n1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.3 %

Procedure:
To a solution of ethyl 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoate (example 147b, 0.295 g, 667 μmol) in a mixture of THF (4 ml)/Water (2 ml) was added LiOH monohydrate (83.9 mg, 2.00 mmol). The reaction mixture was sonicated for a few minutes to dissolved solids. The reaction was stirred at room temperature overnight. The reaction was then concentrated in vacuo and the obtained residue was dissolved in ethyl acetate. The organic phase was extracted with a 0.1M aqueous solution hydrochloric acid. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness to yield the title compound (280 mg, 100%) as a crude yellow oil which was used without any purification. MS (ESI, m/z): 415.5 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:7][S:8](=[S:11])([O-:10])=[O:9].[Na+].O>CN(C=O)C>[CH3:7][S:8](=[S:11])([O:10][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[O:9]
Reactant: CC(C)CCBr
Reactant: CS(=O)([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCOS(C)(=O)=S
Temperature: 50 °C
Yield: 69.9 %

Procedure:
The reaction mixture of 1-bromo-3-methylbutane (1.7520 g, 0.0116 mol) and sodium methanethiosulfonate (1.554 g, 0.0116 mol) in dry DMF (5 mL) was heated at 50° C. for 2 hr. At room temperature, water (15 mL) was added and the mixture was extracted with ether (3×30 mL). The combined extracts were washed with brine, dried, concentrated. The residue was subjected to flash column chromatography on silica gel with EtOAc-hexanes (1:4). The product was obtained as a colorless liquid (1.4777 g, 70%). IR (film): 3030 (w), 3011 (w), 2958 (st), 2932 (st), 2873 (st), 1468 (m), 1410 (w), 1388 (w), 1367 (w), 1319 (st), 1136 (st), 955 (st), 748 cm−1 (st); 1H NMR (200 MHz, CDCl3): δ 3.33 (s, 3H, CH3SO2S); 3.19 (t, J=7.1 Hz, 2H, SCH2CH2), 1.70-1.58 (m, 3H, SCH2CH2CHMe2), 0.95 (d, J=5.3 Hz, 6H, CHMe2); 13C NMR (50 MHz, CDCl3): δ 50.60, 38.19, 34.59, 27.40, 22.06.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[N:20]=[C:21]([O:22]C)[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1.Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1nc(SC)nc2c1c(C)cn2Cc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Temperature: 105 °C
Reaction time: 36 h
Yield: 48 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-4-methoxy-5-methyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidine (0.671 g) was dissolved in dioxane (8 ml) followed by addition of 4,4'-thiobis(6-t-butyl-m-cresol) (7.2 mg). Then, 0.5N-hydrochloric acid (1.12 ml) was added and the mixture was stirred at 105° C. for 36 hours. Thereafter, 0.5 N-hydrochloric acid (1.12 ml) was added again and the mixture was further stirred at the same temperature as above for 24 hours. To this reaction mixture was added water (30 ml) and the resulting precipitate was collected by filtration and dried. The dried precipitate was purified by flash column chromatography (chloroform) to provide the title compound (0.312 g). 1H-NMR (DMSO-d6) 8: 2.24(3H,s), 2.51(3H,d,J=l.OHz), 5.33(2H,s), 6.83(1H,d,J=l.OHz), 7.43(2H,d,J=8.2Hz), 7.60(2H,d,J=8.6Hz), 7.71(2H,d,J=8.2Hz), 7.73(2H,d,J=8.6Hz), 12.01(1H,s).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20])=[CH:12][CH:11]=2)[CH2:5][N:4]1[CH2:28][CH3:29])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:7][CH:6]([NH:8][C:9](=[S:39])[C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17]/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20])=[CH:12][CH:11]=2)[CH2:5][N:4]1[CH2:28][CH3:29])[CH3:2]
Reactant: CCN1CC(NC(=O)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN1CC(NC(=S)c2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Yield: 139.6 %

Procedure:
To a solution of N-(1,2-diethyl-4-pyrazolidinyl)-4-geranyloxybenzamide (1.50 g) in toluene (50 ml) was added Lawesson's reagent (0.76 g). After the reaction solution was refluxed with heating for 30 minutes, ethyl acetate was added thereto. Then, the reaction solution was washed with aqueous sodium bicarbonate solution and then with brine. Its organic layer was concentrated under a vacuum and thus obtained residue was pulled by silica gel column chromatography (chloroform:methanol=30:1), thereby yielding 1.09 g (70%) of the aimed compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38]1[CH2:43][CH2:42][NH:41][C@H:40]([CH3:44])[CH2:39]1)([CH3:37])[CH3:36].C(N(CC)CC)C>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:26]([CH3:27])=[CH:25][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:41]4[CH2:42][CH2:43][N:38]([CH:35]([CH3:37])[CH3:36])[CH2:39][C@H:40]4[CH3:44])[N:19]=3)[S:17][C:13]=2[C:12]=1[C:28]1[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN[C@H](C)C1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)n3)sc2c1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(C)C)C[C@H]4C)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 96 h

Procedure:
To (S)-methyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyrimidin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (40.0 mg, 0.077 mmol) was added (R)-1-isopropyl-3-methylpiperazine (33.1 mg, 0.232 mmol) in 1,4-dioxane (1 mL) and triethylamine (15.7 mg, 22 μL, 0.155 mmol). The reaction mixture was stirred at 60° C. for 4 d, after which the reaction mixture was filtered through Celite (ethyl acetate eluent), concentrated, and used without further purification. LCMS-ESI+ calc'd for C33H41ClN5O3S (M+H+): 622.3; Found: 622.2 (M+H+).
Reaction SMILES: CS(O[C@@H:6]1[CH2:15][O:14][C@H:13]2[C@@H:8]([O:9][CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:11][CH2:12]2)[CH2:7]1)(=O)=O.[N-:22]=[N+]=[N-].[Na+].CP(C)C.[N-]=[N+]=[N-]>CN(C=O)C.C1COCC1>[C:16]1([CH:10]2[O:9][C@H:8]3[CH2:7][C@@H:6]([NH2:22])[CH2:15][O:14][C@@H:13]3[CH2:12][O:11]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Agent: CP(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N[C@H]1CO[C@@H]2COC(c3ccccc3)O[C@H]2C1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a stirred solution of (4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl methanesulfonate (109 mg, 0.347 mmol) under nitrogen in anhydrous DMF (2.0 mL) was added sodium azide (90 mg, 1.387 mmol). The mixture was heated to 80° C. After 24 hours, the mixture was concentrated under reduced pressure. The resultant oil was chromatographed using a Biotage™ 10 g silica gel cartridge eluted with 0-50% EtOAc in 1:1 Hexane/DCM over 20 column volumes. The product fractions were combined and concentrated under reduced pressure. The resultant white solid (67 mg, 0.256 mmol) was dissolved in anhydrous THF (2.0 mL) under nitrogen and a IM solution of trimethylphosphine (0.51 mL, 0.51 mmol) was added. The mixture was allowed to stir at room temperature for 40 minutes until the azide was consumed, then saturated aqueous ammonium hydroxide (0.5 mL) was added. After stirring for 30 minutes, the mixture was concentrated under reduced pressure and dried under high vacuum. The resultant residue was dissolved in acetonitrile (2 mL), frozen at −78° C., and lyophilized to dryness to provide the title compound as a white solid. LC-MS: calculated for C13H17NO3 235.12, observed m/e: 236.19 (M+H)+ (Rt 0.45/4 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:16](Cl)([Cl:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]([Cl:18])=[O:17])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(Nc2ccccc2)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(N(C(=O)Cl)c2ccccc2)c1
Yield: 99 %

Procedure:
According to the procedure of Example 15, Step A, 5.5 g (27.9 mmole) of N-(3,5-dimethylphenyl)aniline, 27.9 mL of 1.93M phosgene in toluene and 15 mL of toluene gave 7.15 g (99%) of a red oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1.[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>C(O)C>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][CH2:2][C:3]1[S:4][C:5]([C:8]2[N:9]=[C:10]([N:13]=[C:14]([NH2:16])[NH2:15])[S:11][CH:12]=2)=[CH:6][N:7]=1)#[N:22]
Reactant: NCc1ncc(-c2csc(N=C(N)N)n2)s1
Reactant: CSC(=NC#N)SC
Solvent: CCO
Product: CSC(=NC#N)NCc1ncc(-c2csc(N=C(N)N)n2)s1

Procedure:
A mixture of 4-(2-aminomethylthiazol-5-yl)-2-(diaminomethyleneamino)thiazole (0.45 g) and dimethyl N-cyanodithioiminocarbonate [(CH3S)2C=N--CN] (0.26 g) in ethanol (10 ml) was refluxed for 5 hours with stirring to give 4-[2-(3-cyano-2-methylisothioureido)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole as a crude product. After cooling to ambient temperature, 40% aqueous methylamine by weight (1.4 ml) was added to the suspension and the mixture was stirred for 12 hours at ambient temperature, The solvent was evaporated in vacuo and the residue was mixed with water (5 ml) and ethyl acetate (5 ml). The resulting precipitate was collected and recrystallized from aqueous N,N-dimethylformamide to give 4-[2-(2-cyano-3-methylguanidino)methylthiazol-5-yl]-2-(diaminomethyleneamino)thiazole (0.35 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15](O)=[O:16])=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[OH:27][CH:28]1[CH2:31][NH:30][CH2:29]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:14]([NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[C:15]([N:30]2[CH2:31][CH:28]([OH:27])[CH2:29]2)=[O:16])=[CH:20][CH:21]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC(O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(S)-[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (100 mg, 0.28 mmol), 3-hydroxyazetidine hydrochloride (Heterocycles, 2002, 56(1-2), 433-442; 30 mg, 0.28 mmol) and HOBt (37 mg, 0.28 mmol) were dissolved in DMF (5 ml) and DIPEA (0.14 ml, 0.83 mmol). After 5 min, EDCI (69 mg, 0.36 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the residue triturated with water. Purification by chromatography on silica gel eluting with methanol:dichloromethane (1:49 to 3:97) gave the title compound as a yellow solid. δH (CD3OD): 3.08-3.21 (2H, m), 3.58-3.63 (0.5H, m), 3.84-3.91 (0.5H, m), 4.03-4.09 (0.5H, m), 4.25-4.32 (0.5H, m), 4.38-4.94 (4H, m), 7.03-7.12 (2H, m), 7.15-7.19 (1H, m), 7.30-7.38 (2H, m), 7.68 (1H, s), 8.59 (1H, s); RT=3.32 min.
Reaction SMILES: B#B.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[C:12](O)=[O:13]>O1CCCC1>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[C:4]1[CH2:12][OH:13]
Reactant: O=C(O)c1cc2ccccc2o1
Agent: B#B
Solvent: C1CCOC1
Product: OCc1cc2ccccc2o1
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
1 Molar diborane in tetrahydrofuran (61.6 mL, 61.6 mmol) was added dropwise over 10 minutes to a stirred solution of benzofuran-2-carboxylic acid (5.00 g, 30.8 mmol) in tetrahydrofuran (50 mL) at 0° C. Stirring was continued at 0° C. for 30 minutes, then at room temperature for 18 hours. The reaction mixture was quenched carefully by slow addition of 1:1 THF/H2O, and extracted with ether. The organic extracts were dried (MgSO4) and concentrated to afford 3.58 g (78%) of product as a colorless oil.
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:28].C(O)(=O)C>C(Cl)Cl>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:22][C@@H:5]1[Br:28])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.67 h

Procedure:
To β-D-glucose pentaacetate (5 g, 12.81 mmol) was added 33% HBr in acetic acid (30 mL, 192 mmol) at rt. After stirring for 40 min, the mixture was diluted with CH2Cl2 (150 mL) and washed with ice cold water until the washings were neutral pH. The organic layer was dried over MgSO4, filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 2.06 (s, 3H), 2.08 (s, 3H), 2.12 (s, 3H), 2.13 (s, 3H), 4.15 (d, J=11.1, 1H), 4.31-4.37 (m, 2H), 4.86 (dd, J=9.9, 4.0, 1H), 5.19 (t, J=9.8, 1H), 5.58 (t, J=9.8, 1H), 6.63 (d, J=4.0, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:4](F)[CH:3]=1.[C-:15]#[N:16].[Na+]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:4]([CH:3]=1)[C:15]#[N:16]
Reactant: Fc1cc(Br)ccc1-c1ccccn1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1-c1ccccn1
Temperature: 180 °C
Yield: 79.2 %

Procedure:
2-(4-Bromo-2-fluorophenyl)pyridine (1.0 g, 3.9 mmol) and sodium cyanide (214 mg, 4.3 mmol) were combined in DMSO (20 mL) under argon. The reaction mixture was heated at 180° C. overnight. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (100 mL), and washed with H2O (3×100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with 1:9 EtOAc:Hexane. to afford 5-bromo-2-pyridin-2-ylbenzonitrile (800 mg, 80%). MS 262.1 (M++H).