Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.ClC1C=CC=CN=1.FC1(F)C(=C)CN(C(OC(C)(C)C)=O)C1=O.[Cl-].[NH4+].[Cl:38][C:39]1[C:44]([C:45](=O)[C:46]([F:59])([F:58])[C:47](=[CH2:57])[CH2:48][NH:49]C(=O)OC(C)(C)C)=[CH:43][CH:42]=[CH:41][N:40]=1.ClC1C(C2(O)C(F)(F)C(=C)CN2C(OC(C)(C)C)=O)=CC=CN=1.Cl>O1CCCC1.C(O)(=O)C.CCCCCC>[Cl:38][C:39]1[C:44]([C:45]2[C:46]([F:59])([F:58])[C:47](=[CH2:57])[CH2:48][N:49]=2)=[CH:43][CH:42]=[CH:41][N:40]=1
Reactant: C=C(CNC(=O)OC(C)(C)C)C(F)(F)C(=O)c1cccnc1Cl
Agent: C=C1CN(C(=O)OC(C)(C)C)C(=O)C1(F)F
Agent: C=C1CN(C(=O)OC(C)(C)C)C(O)(c2cccnc2Cl)C1(F)F
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=C1CN=C(c2cccnc2Cl)C1(F)F
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Under a nitrogen atmosphere, to a solution of diisopropylamine (30.8 g) in anhydrous tetrahydrofuran (300 mL) was added dropwise a 1.61 mol/L hexane solution (160 mL) of n-butyllithium at −78° C., and the mixture was stirred at the same temperature for 15 min. To the obtained solution was added a solution of 2-chloropyridine (30.9 g) in anhydrous tetrahydrofuran (30 mL) at the same temperature over 30 min, and the mixture was stirred for 2 hr. To the obtained suspension was added dropwise a solution of tert-butyl 3,3-difluoro-4-methylene-2-oxopyrrolidine-1-carboxylate (30.1 g) in anhydrous tetrahydrofuran (30 mL) at the same temperature, and the mixture was stirred for 3 hr. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1) to give a mixture of tert-butyl [4-(2-chloropyridin-3-yl)-3,3-difluoro-2-methylene-4-oxobutyl]carbamate and tert-butyl 2-(2-chloropyridin-3-yl)-3,3-difluoro-2-hydroxy-4-methylenepyrrolidine-1-carboxylate (yield 23.8 g). To a solution of the obtained mixture (23.7 g) in acetic acid (70 mL) was added dropwise concentrated hydrochloric acid (18 mL). The obtained mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=3:1) to give the title compound as a yellow oil (yield 12.1 g, 2 step yield 41%).
Reaction SMILES: [C:1]([O:7][C:8]1[CH:21]=[C:20]([CH:22]=C)[C:11]2[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][S:14][C:10]=2[CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC(C)=[O:26].C[N+]1([O-])CCOCC1>O=[Os](=O)(=O)=O.O.CC#N>[C:1]([O:7][C:8]1[CH:21]=[C:20]([CH:22]=[O:26])[C:11]2[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][S:14][C:10]=2[CH:9]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: C=Cc1cc(OC(=O)C(C)(C)C)cc2scc(CC(=O)OC)c12
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1csc2cc(OC(=O)C(C)(C)C)cc(C=O)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 3-(2-methoxy-2-oxoethyl)-4-vinyl-1-benzothiophen-6-yl pivalate (480 mg), acetone (500 μL), water (500 μL) and CH3CN (500 μL) were added OsO4 (7% microcapsule, 524 mg) and NMO (507 mg) at room temperature. The mixture was stirred at room temperature for 20 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. To a mixture of the residue, THF (3 mL) and water (3 mL) was added NaIO4 (403 mg, 1.88 mmol) at room temperature. After stirring at room temperature for 1 h, the m mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (152 mg).
Reaction SMILES: [C:1]1([S:7]([CH:10]([NH2:30])[C:11]2[N:16]([CH3:17])[C:15]([C:18]([OH:20])=[O:19])=[C:14]([O:21]CC3C=CC=CC=3)[C:13](=[O:29])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>C(O)(=O)C>[C:1]1([S:7]([CH:10]([NH2:30])[C:11]2[N:16]([CH3:17])[C:15]([C:18]([OH:20])=[O:19])=[C:14]([OH:21])[C:13](=[O:29])[CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Temperature: 80 °C
Yield: 47.1 %

Procedure:
To a stirred solution of 6-(benzene sulfonyl amino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01) (430.0 mg, 1.005 mmol) in acetic acid (15 mL) was added sulfuric acid (0.011 mL) and the reaction mixture was heated at 80° C. for 24 h. After completion of the reaction, it was concentrated and the reaction mixture was quenched with ice and solid was precipitated. Resulted solid was filtered and dried to get the crude product. It was then washed with 20% methanol and ethyl acetate to get 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01) (160.0 mg, 47.07%) as an off white solid.
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([CH2:16][NH:17][C:18](=[O:37])[CH2:19][C@H:20]1[O:25][C:24](=[O:26])[N:23]([CH3:27])[C@@H:22]([C:28]2[CH:33]=[CH:32][C:31]([CH:34]=[N:35][NH2:36])=[CH:30][CH:29]=2)[CH2:21]1)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1)(=[O:8])=[O:7].[ClH:39]>>[ClH:39].[NH2:36][N:35]=[CH:34][C:31]1[CH:30]=[CH:29][C:28]([C@H:22]2[CH2:21][C@@H:20]([CH2:19][C:18]([NH:17][CH2:16][C@@H:4]([C:3]([OH:38])=[O:2])[NH:5][S:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)(=[O:8])=[O:7])=[O:37])[O:25][C:24](=[O:26])[N:23]2[CH3:27])=[CH:33][CH:32]=1
Reactant: COC(=O)[C@H](CNC(=O)C[C@@H]1C[C@H](c2ccc(C=NN)cc2)N(C)C(=O)O1)NS(=O)(=O)c1cccc(C)c1
Agent: Cl
Product: Cc1cccc(S(=O)(=O)N[C@@H](CNC(=O)C[C@@H]2C[C@H](c3ccc(C=NN)cc3)N(C)C(=O)O2)C(=O)O)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 90 %

Procedure:
Cis-3-[[[4-[4-(aminoiminomethyl)phenyl]tetrahydro-3-methyl-2-oxo-2H-1,3-oxazin-6-yl]acetyl]amino]-N-[(3-methylphenyl)sulfonyl]-L-alanine methyl ester(30 mg, 0.06 mmol) was dissolved in 3N HCl(3 ml). The resulting solution was stirred at rt for 36 hrs and then concentrated to yield the acid as an amorphous solid(90 mg, 90% yield). The acid was further purified by reverse HPLC using water and 0.1% TFA in acetonitrile as eluent. MS(ESI) Calc. for (M+1)+ : 532. Found: 532.
Reaction SMILES: S([O:5][CH2:6][C@@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)(=O)C.[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[SH:33].C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(Cl)Cl.CN(C)C=O>[CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[S:33][C:6](=[O:5])[C@@H:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: Sc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)Sc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-Boc-D-phenylalaninol mesylate (0.3 g, 0.9 mmol), dimethylformamide (10 mL), 2-napthalenethiol (0.22 g, 1.39 mmol), diisopropylethylamine (1.39 mmol) and sodium iodide (0.14 g, 0.93 mmol) was kept at 80° C. for 18 hr, cooled to room temperature and methylene chloride (25 ml) was added. This mixture was washed with water (2×10 mL), 1 M sodium hydroxide (3×10 mL) and brine (2×15 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate adsorbed onto silica gel and applied to a column prepacked with silica gel. The title compound (121 mg) was eluted with hexane:ethyl acetate (90:10, v:v) to afford a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][SH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN(C(C)C)C(C)C.[Na+].[I-].[CH2:27](Br)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].Cl>CC#N.O>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][S:14][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CSCC(=O)c1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 124.5 %

Procedure:
To a solution of the N-Boc cysteine methyl ester (2.05 ml, 9.93 mmol) in MeCN (20 ml) at 0° C. were added DIPEA (3.55 ml, 20.1 mmol), NaI (0.48 g, 3.20 mmol), and then a solution of phenacyl bromide (2.41 g, 12.1 mmol) in MeCN (4 ml). The mixture was stirred at room temperature for 19 h. Water (100 ml) and 1N aqueous HCl. (30 ml) was added, and the product was extracted (3×AcOEt). The combined extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to yield 4.37 g of an oil. Crystallization from AcOEt (approx 10 ml) and heptane (approx 40 ml) at −20° C. overnight yielded 3.49 g (99%) of the title methyl ester as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH3:11][N:12]([CH3:34])[C:13]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][CH2:17][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)(O)[CH2:15][CH2:14]1.FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>ClCCl.O=O>[CH3:27][O:26][C:22]1[CH:21]=[C:20]([C:16]2([C:3]3[NH:4][C:5]4[C:10]([C:2]=3[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:15][CH2:14][C:13]([N:12]([CH3:11])[CH3:34])([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18][CH2:17]2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(C2(O)CCC(c3ccccc3)(N(C)C)CC2)c1
Reactant: Cc1c[nH]c2ccccc12
Agent: O=O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(C2(c3[nH]c4ccccc4c3C)CCC(c3ccccc3)(N(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-methyl-1H-indole (393 mg, 3 mmol) and the 4-dimethylamino-1-(3-methoxyphenyl)-4-phenylcyclohexanol (651 mg, 2 mmol) mixture were dissolved in absolute dichloromethane (50 ml) with exclusion of oxygen, mixed with trifluoromethane sulphonic acid (581 μl, 3 mmol) and stirred for 16 h at room temperature. For work up the batch was mixed with 5N NaOH (50 ml) and stirred for 1 h at room temperature. The aqueous phase was separated and extracted with dichloromethane (3×25 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. A raw product was isolated that was purified by chromatography [silica gel 60 (50 g); ethyl acetate (500 ml)]. The product was obtained as a white solid with a yield of 90 mg (10%) and a melting point of 278-281° C. This concerned one of two possible diastereoisomers.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:20]3[C:21]([CH3:27])=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)([C:14]3[N:18]([CH3:19])[N:17]=[N:16][CH:15]=3)[OH:13])[CH:10]=2)[N:5]=[C:4]([O:28][CH3:29])[C:3]=1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C[C:76]([N:78](C)C)=O>[C-]#N.[Zn+2].[C-]#N.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][C:21]1[C:20]([C:12]([OH:13])([C:14]2[N:18]([CH3:19])[N:17]=[N:16][CH:15]=2)[C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=2)[N:5]=[C:4]([O:28][CH3:29])[C:3]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=2)=[C:2]3[C:76]#[N:78])=[CH:25][CH:24]=[C:23]([CH3:26])[N:22]=1
Reactant: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: CC(=O)N(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(C#N)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 125 °C

Procedure:
(4-Chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (250 mg, 0.44 mmol, Example 77A), zinc cyanide (90 mg, 0.77 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos, 40 mg, 0.084 mmol), zinc powder (8 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0), (Pd2(dba)3; 60 mg, 0.066 mmol) were added to a large microwave vial, then dimethylacetamide (7 mL, degassed with argon) was added and the vial was sealed and evacuated. The mixture was heated to 125° C. in an aluminum heating mantle. The mixture was cooled to 80° C. and then filtered through a Celite® pad and rinsed with EtOAc-MeOH (10:1, v/v) and the light brown filtrate was concentrated under vacuum to afford a brown oil. The crude material was chromatographed directly on silica gel (100% DCM increasing to 10% MeOH-DCM) which provided the product contaminated with dimethylacetamide. This material was further purified by RP-HPLC to the title compound as a white foam. MS m/e 559.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ ppm 8.05 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 7.42-7.34 (m, 2H), 7.06 (s, 1H), 4.37 (s, 2H), 4.13 (s, 3H), 3.94 (s, 3H), 2.77 (s, 3H), 2.62 (s, 3H). The racemic material was separated into its individual enantiomers using the following conditions: Chiralpack OD, 80% heptanes:20% ethanol; wavelength at 220 nM to provide the two enantiomers. The first eluting enantiomer was Example 78B and the second eluting enantiomer was Example 78C.
Reaction SMILES: I[C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[CH3:7].C1COCC1.Br[C:15]1[S:19][C:18]([C:20]2[N:24]3[N:25]=[C:26]([CH3:34])[CH:27]=[C:28]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]3=[N:22][C:21]=2[CH3:35])=[C:17]([CH3:36])[CH:16]=1>CCOC(C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:8][C:3]1[C:2]([C:15]2[S:19][C:18]([C:20]3[N:24]4[N:25]=[C:26]([CH3:34])[CH:27]=[C:28]([CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[C:23]4=[N:22][C:21]=3[CH3:35])=[C:17]([CH3:36])[CH:16]=2)=[C:6]([CH3:7])[O:5][N:4]=1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Reactant: Cc1noc(C)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4c(C)noc4C)cc3C)c(C)nc12
Temperature: 50 °C
Yield: 71.1 %

Procedure:
To a flask of 4-iodo-3,5-dimethyl-isoxazole (0.34 g, 1.53 mmol) is added a solution of Rieke® zinc 5 g/100 mL in THF (3 mL, 2.29 mmol). The slurry is heated at a reflux for 4 hours, the zinc is allowed to settle and the solution transferred to a flask of 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.30 g, 0.76 mmol) and PdCl2(dppf) (0.028 g, 0.038 mmol). The solution is heated at 50° C. overnight, diluted with EtOAc (20 mL), washed with 0.1 M HCl (15 mL), water (15 mL), brine (15 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15%-30% EtOAc/hexane gradient) furnish the title compound (0.22 g, 0.54 mmol, 71%). 1H NMR (CDCl3), δ 0.92 (t, J=7.5 Hz, 6H), 1.78-1.96 (m, 4H), 2.21 (s, 3H), 2.47 (s, 3H), 2.53 (s, 3H), 2.56 (s, 3H), 2.61 (s, 3H), 3.33-3.42 (m, 1H), 6.72 (s, 1H), 6.98 (s, 1H). LC/MS (m/z): calcd. for C23H28N4OS (M+H)+: 409.3; found: 409.2.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18].[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCC(=O)O
Reaction time: 1 h

Procedure:
A 100 mL media bottle equipped with a septum cap and stir bar was charged with of t-BOC-GlyGly-Ama-diEt (5.12 g, 13.14 mmol) and CH2Cl2(15 mL). With vigorous stirring, TFA (25 mL in 25 mL CH2Cl2) was added dropwise. After 1 hour the reaction was complete, the TFA was removed in vacuo and the trifluoroacetate salt precipitated with Et2O. The TFA-GlyGly-Ama-diEt salt was collected by filteration, washed with Et2O and recrystallized from absolute EtOH:ether (7:3 v/v). The white crystals were dried in vacuo to give 5.21 g of product: 1H NMR (DMSO-d6) δ 8.96 (br d, 1, —NHCH—), 8.63 (br t, 1, —NHCH2—), 8.02 (v br s, 3, NH3CH2), 5.09 (d, 1, CH(CO2Et), 4.12−4.24 (m, 4, OCH2CH3), 3.94 (br d, 2, —NHCH2—), 3.59 (br s, 2, —NHCH2—), 1.21 (t, 6, OCH2CH3). 13C NMR (CDCl3) δ 168.8, 166.4, 158.3, 158.0, 119.3, 115.4, 61.9, 56.3, 41.5, 13.9.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[C:7]1[S:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([C:3]([OH:2])=[O:4])[N:6]=1
Reactant: CNC
Reactant: COC(=O)c1nc(Br)sc1-c1ccccc1
Product: CN(C)c1nc(C(=O)O)c(-c2ccccc2)s1

Procedure:
prepared by reaction of 2-bromo-5-phenyl-thiazole-4-carboxylic acid methyl ester with dimethylamine. LC-MS: tR=0.81 min; [M+H]+=249.1.
Reaction SMILES: N(CCN)=[N+]=[N-].C(N(CC)CC)C.[CH:14]1[C:19](N=C=S)=[CH:18][C:17]2[C:23]([O:25][C:26]3([C:36]4[CH:37]=[CH:38][C:39]([OH:41])=[CH:40][C:35]=4[O:34][C:28]4[CH:29]=[C:30]([OH:33])[CH:31]=[CH:32][C:27]3=4)[C:16]=2[CH:15]=1)=[O:24]>ClCCl>[CH:14]1[CH:19]=[CH:18][C:17]([C:23]([OH:25])=[O:24])=[C:16]([C:26]2[C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[O:34][C:35]3[C:36]=2[CH:37]=[CH:38][C:39]([CH:40]=3)=[O:41])[CH:15]=1
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Agent: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Reaction time: 21 h
Yield: 99.1 %

Procedure:
Under argon atmosphere, to a solution of 2-azidoethylamine (16) (˜50%, 1H NMR) (synthesized by the method described in Non-Patent Document: R. Srinivasan, L. P. Tan, H. Wu, P. Yang, K. A. Kalesh, S. Q. Yao, Org. Biomol. Chem. 2009, 7, 1821-1828) (200 mg, ˜1.16 mmol) in dichloromethane (5 mL) were successively added triethylamine (70.0 μL, 502 μmol) and fluorescein isothiocyanate isomer I (FITC, 17, commercial product) (90%, HPLC) (100 mg, 231 μmol) at room temperature. After stirring for 21 hours at the same temperature, the reaction solution was concentrated under reduced pressure using an evaporator. The residue was purified by flash column chromatography (silica-gel 30 g, dichloromethane/methanol=9/1) to give 1-(2-azidoethyl)-3-(5-fluoresceinyl)thiourea (18) (109 mg, 229 μmol, 99.2%) as an orange solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:19])[C:14](OCC)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[H-].S(=O)(=O)(O)O>CCOCC>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH3:19])[CH2:14][OH:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)c1ccc(Oc2ccc(F)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(CO)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Ethyl 2-[4-(4-fluorophenoxy)phenyl]propionate (1.3 g.) in dry ether (5 ml.) was added dropwise to lithium aluminium hydride (200 mg.) in dry ether (5 ml.). After refluxing for 1 hour the excess hydride was decomposed with dilute sulfuric acid, and the ether layer was distilled to give 2-[4-(4-fluorophenoxy)phenyl]propanol, b.p. 151°-152°C./0.6 mm.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]3[N:8]([CH:11]=[N:12][N:13]=3)C=[N:10][C:5]=2[S:4][CH:3]=1.CNCCN>CO.[Cl-].[NH4+]>[Br:1][C:2]1[C:6]([C:7]2[NH:8][CH:11]=[N:12][N:13]=2)=[C:5]([NH2:10])[S:4][CH:3]=1
Reactant: Brc1csc2ncn3cnnc3c12
Agent: CNCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Nc1scc(Br)c1-c1nnc[nH]1
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
9-Bromothieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine (551 mg, 2.16 mmol) and N-methylethane-1,2-diamine (1 ml, 11.3 mmol) in methanol (20 ml) was placed into a preheated oil bath at 60° C. After stirring for 15 min, the solution was diluted with saturated ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 525 mg (99% yield) of 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine as a brown solid. Method [8] retention time 2.25 min by HPLC (M+245 and 247).
Reaction SMILES: [C:1]([C:3]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:11]>CO.[Pd]>[ClH:11].[ClH:11].[NH2:2][CH2:1][C:3]1[C:8]([S:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CSc1cccnc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CSc1cccnc1CN

Procedure:
A stirred solution of 659 mg (4.39 mmol) of 2-cyano-3-methylthiopyridine 3-1 in 25 mL of methanol and 5 mL of 6M aq. HCl was hydrogenated over 659 mg of 10% palladium on carbon at 55 psi for 5 h. The catalyst was removed by filtration and the solvents concentrated at reduced pressure. The resulting material was diluted with methanol and concentrated (2×) to give 3-2 as an off-white solid: 1H NMR (CD3OD): δ 2.58 (s, 3H), 4.28 (s, 2H), 7.43 (m, 1H), 7.86 (dd, J 1.3 and 8.1 Hz, 1H), 8.43 (dd, J=1.3 and 4.8 Hz, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.[S:10](Cl)(Cl)=O>C1C=CC=CC=1>[SH:10][CH2:2][C:3]1[CH:4]=[N+:5]([O-:9])[CH:6]=[CH:7][CH:8]=1
Reactant: [O-][n+]1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: [O-][n+]1cccc(CS)c1

Procedure:
A solution of 30 g. of 3-hydroxymethylpyridine-N-oxide in 200 ml. of benzene and 18.4 g. of thionyl chloride was refluxed 2 hours, cooled and filtered to give 3-mercaptomethylpyridine-N-oxide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.N[C:14]1[CH:15]=C(C(C)=[CH:22][CH:23]=1)C(OC)=O>>[CH3:12][C:3]1[C:2]([N:1]2[CH:22]=[CH:23][CH:14]=[CH:15]2)=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][OH:7]
Reactant: COC(=O)c1cc(N)ccc1C
Reactant: COC(=O)c1cccc(N)c1C
Product: Cc1c(CO)cccc1-n1cccc1

Procedure:
When the same reaction as in Referential Example 18 is carried out using methyl 3-amino-2-methylbenzoate instead of the starting methyl 3-amino-6-methylbenzoate, 2-methyl-3-(1-pyrrolyl)benzyl alcohol is obtained.