Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:19][C:20]([CH3:22])=[CH2:21])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:23])[CH:3]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:20](=[CH2:21])[CH2:19][N:8]([C:6]1[CH:5]=[C:4]([CH3:23])[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=2)[N:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)CN(c1ccc(C(F)(F)F)cc1)c1cc(C)cc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 85 °C
Yield: 59.9 %

Procedure:
To a degassed solution of (6-chloro-4-methyl-pyridin-2-yl)-(2-methyl-allyl)-(4-trifluoromethyl-phenyl)-amine (340 mg, 1.0 mmol), 4-trifluoromethylbenzeneboronic acid (230 mg, 1.2 mmol), 2N Na2CO3 (1.5 mL) in DME (10 mL) was added tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) under argon. The mixture was heated to 85° C. for 4 h, cooled to room temperature, diluted with water, and extracted with methylene chloride (3×). The organic solution was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% methylene chloride in methylene chloride) to give the product as a white solid (270 mg, 60%). 1H NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.91 Hz, 2H), 7.69 (d, J=8.29 Hz, 2H), 7.59 (d, J=8.67 Hz, 2H), 7.39 (d, J=8.67 Hz, 2H), 7.11 (s, 1H), 6.66 (s, 1H), 4.86 (s, 2H), 4.70 (s, 2H), 2.30 (s, 3H), 1.81 (s, 3H). MS m/e 451.2 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:30]=[N+:31]([O-:54])[CH:32]=[C:33]([Cl:53])[C:34]=1[CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:47])[F:46])=[C:40]([O:48][CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH:39]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:16]([O:18][CH2:19][C:20]([O:22][C@H:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH:45]([F:46])[F:47])=[C:40]([O:48][CH2:49][CH:50]2[CH2:51][CH2:52]2)[CH:39]=1)[CH2:35][C:34]1[C:33]([Cl:53])=[CH:32][N+:31]([O-:54])=[CH:30][C:29]=1[Cl:28])=[O:21])=[O:17])[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)OCC(=O)O)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1N(C(=O)OC(C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
A mixture of 2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetic acid (0.192 g, 0.476 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.200 g, 0.476 mmol), EDC (0.274 g, 1.428 mmol), and DMAP (0.058 g, 0.476 mmol) in DCM (20 ml) was stirred at RT for 2 hours. The mixture was washed with HCl 1N and with NaHCO3 5%; the organic layer was dried over Na2SO4, and the solvent was removed. The crude was purified by flash chromatography on silica gel cartridge (DCM:MeOH=99:1) to afford (S)-4-(2-(2-(3-(N-(tert-butoxycarbonyl)methylsulfonamido)-4-methoxybenzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.296 g, 0.367 mmol, 77% yield, MS/ESI+ 805.0 [MH]+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([CH2:14][CH3:15])[CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][S:2]([CH3:1])(=[O:4])=[O:3])=[C:9]([CH2:14][CH3:15])[CH:8]=1
Reactant: CCc1cc(Br)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1NS(C)(=O)=O
Reaction time: 1 h

Procedure:
Methane sulfonyl chloride (1.93 ml, 0.025M) was added to a solution of 4-bromo-2-ethylaniline (5.0 g, 0.025M) and pyridine (2.02 ml, 0.025M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a clear oil (4.77 g). 1H NMR (CDCl3): δ 1.12 (t, J=8.60 Hz, 3H), 2.91 (q, 2H), 3.06 (s, 3H), 6.81 (d, J=7.54 Hz, 1H), 7.05 (d, J=7.54 Hz, 1H), 7.26 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.[N:8]([O-])=[O:9].[Na+]>S(=O)(=O)(O)O.N([O-])=O.[Na+]>[CH3:7][C:4]1[N:3]=[C:2]([NH:1][N:8]=[O:9])[S:6][N:5]=1
Reactant: Cc1nsc(N)n1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nsc(NN=O)n1
Yield: 50831.3 %

Procedure:
First, 11.5 g (0.1 mol) of 5-amino-3-methyl-1,2,4-thiadiazole was dissolved in 100 mL of 2N sulfuric acid. While the mixture was stirred, an aqueous sodium nitrite solution (containing 8.0 g (0.116 mmol) of sodium nitrite in 20 mL of water) was added dropwise to the mixture at 0° C. or less. After completion of dropwise addition, the resultant solution was continuously stirred further for one hour at 0° C. The crystals precipitated were collected by filtration and washed with ice cold water. The crystals were dried in the air at room temperature overnight to obtain 8.5 g (56% in yield) of 3-methyl-5-nitrosoamino-1,2,4-thiadiazole. Next, 7.2 g (0.05 mol) of the obtained thiadiazole was dissolved in 50 mL of methanol at room temperature. While the resultant solution was stirred, 3 mL of concentrated sulfuric acid was added dropwise to the solution at 5° C. or less. After completion of dropwise addition, the solution was continuously stirred further at 5° C. or less for one hour or less and at 15 to 20° C. for 2 hours. The crystals precipitated were collected by filtration. The crystals were recrystallized from methanol to obtain 2.5 g (41% in yield) of triazene dissociative direct dye D-5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1.[CH2:18](Br)[C:19]#[CH:20].C[O-].[Na+].[Na]>C1(C)C=CC=CC=1.O.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:20][C:19]#[CH:18])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(C)c1Cl
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: C#CCOc1cc(-n2nc(C)c(Cl)c2C)c(Cl)cc1Cl
Reaction time: 3 h
Yield: 91.2 %

Procedure:
1-(2,4-dichloro-5-hydroxyphenyl)-3,5-dimethyl-4-chloropyrazole (29.2 g) and propargyl bromide (12.0 g) were added to a solution of sodium methoxide which was previously prepared from metallic sodium (2.3 g) and methanol (200 ml). The resulting mixture was heated under reflux, with stirring for 3 hours. To the reaction mixture, after cooling, were added water and toluene to form two layers. The toluene layer as formed was separated, washed with water and then dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (30.1 g) as a pale brown crystalline solid. Recrystallization of this solid from a mixture of cyclohexane/acetone afforded a white crystalline solid. m.p. 156.5°-158° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:8][C@:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C@H:3]1[CH2:4][CH2:5][C@H:6]2[O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1.[CH2:39](OC(OCC)OCC)C.[N-:49]=[N+:50]=[N-:51].[Na+]>C(O)(=O)C>[CH2:10]([N:9]1[C@@H:3]2[C@H:2]([N:1]3[CH:39]=[N:51][N:50]=[N:49]3)[CH2:8][C@@:7]1([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@H:6]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([C:35]([F:38])([F:36])[F:37])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:5][CH2:4]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(CO[C@@H]2CC[C@H]3[C@H](n4cnnn4)C[C@]2(c2ccccc2)N3Cc2ccccc2)cc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 67.2 %

Procedure:
(1R*,2R*,5S*,6R*)-6-Amino-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 108; 209 mg, 0.39 mmol) in triethylorthoformate (3.5 ml, 19.22 mmol) and glacial acetic acid (1 ml) was heated to 90° C. Sodium azide (250 mg, 3.85 mmol) was added and the mixture further heated at 90° C. overnight. The mixture was cooled and partitioned between saturated sodium hydrogen carbonate solution and dichloromethane. The organics were dried (MgSO4) and concentrated in vacuo. The reaction mixture was purified by flash column chromatography [2.5% methanol in dichloromethane] to give the title compound as a cream-coloured foam (154 mg, 56%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:61])([CH3:60])[CH2:48][NH:49]C(OCC1C=CC=CC=1)=O.Cl.NCC(N)=O>>[NH2:49][CH2:48][C:47]([NH:46][C:40]([CH2:39][CH2:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42])([CH3:61])[CH3:60]
Reactant: CC(C)(N)CNC(=O)OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)CN)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]-phenyl}methyl)-5-isopropyl-1H-pyrazole and 2-amino-1-benzyloxycarbonylamino-2-(methyl)propane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:47])/[C:32](/[C:45]#[N:46])=[CH:33]/[C:34]([NH:37]C(=O)OC(C)(C)C)([CH3:36])[CH3:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C(Cl)Cl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[NH2:37][C:34]([CH3:36])([CH3:35])[CH:33]=[C:32]([C:31]([N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][N:8]1[C:4]2=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]2[C:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][C:12]=2[F:24])=[N:9]1)=[O:47])[C:45]#[N:46]
Reactant: CC(C)(/C=C(\C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N)C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R,E)-tert-butyl (5-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl)carbamate (90 mg, 0.14 mmol, 1 equiv) in 16 mL DCM was added 4 mL trifluoroacetic acid dropwise. The resulting solution was stirred for 3 h at room temperature. The solution was concentrated under reduced pressure. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm Sum; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm to give the title compound as a pale light yellow solid.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1>CCO>[C:11]1([C:8]2[S:7][C:6]([CH2:5][C:1]#[N:2])=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ncc(-c2ccccc2)s1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ncc(-c2ccccc2)s1
Temperature: 70 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
NaCN (0.46 g, 9.4 mmol) was added to a solution of 2-(bromomethyl)-5-phenylthiazole (2.0 g, 7.87 mmol) in dry EtOH (10 mL). The resulting reaction mixture was stirred at 70° C. for 2 h and then concentrated under reduced pressure, and diluted with ethyl acetate. The organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 10% EtOAc in petroleum ether) to afford 2-(5-phenylthiazol-2-yl)acetonitrile (350 mg, yield 22%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.56-7.54 (m, 2H), 7.46-7.40 (m, 3H), 4.15 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2S: 200.04. found: 201.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1)#[CH:20].CCN(C(C)C)C(C)C.CCOC(C)=O>C1COCC1.[Cu]I>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:20]#[C:19][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=2)=[CH:13][CH:12]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(CNC(=O)OC(C)(C)C)c1ccc(I)cc1
Reactant: C#Cc1ccc(OCCC)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C#Cc2ccc(C(C)CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.00 g (2.77 mmol) [2-(4-iodo-phenyl)-propyl]-carbamic acid tert-butyl ester (152.8) and 0.44 g (2.77 mmol) 1-ethinyl-4-propoxybenzene in 25 mL THF are added 0.78 mL (5.54 mmol) DIPEA, 40.5 mg (0.06 mmol) [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II) and 10.6 mg (0.055 mmol) CuI. The reaction mixture is stirred at r.t. for 3 h. EtOAc is added and the mixture is washed with diluted aq. ammonia solution (1×) and water (1×), dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, PE/EtOAc 9/1).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][C:5](=[O:6])[NH:4][CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N[C@H](C(O)=O)C[SH:19].C(S)[C@@H](O)[C@H](O)CS.C(O)C(N)(CO)CO.Cl>>[OH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[C@@H:3]2[C@@H:2]([NH:7][C:5]([NH:4]2)=[O:6])[CH2:1][S:19]1)=[O:15]
Reactant: CC1NC(=O)NC1CCCCCC(=O)O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O[C@H](CS)[C@H](O)CS
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 95 °C

Procedure:
The enzyme reaction mixture without cell-free extracts contained 100 μM desthiobiotin. 1000 μM SAM, 200 μM L-cysteine, 50 μM deazariboflavin, 0.6 mg/ml (16 μM) BIOB protein, 10 mM DTT and 0.1 M Tris-HCl/pH 7.5 in total volume of 50 μl. The enzyme reaction mixture in a 300 μl glass spitz tube was brought to anaerobic condition by repeating of weak aspiration and argon pressure under dark. The reaction was started by light irradiation from 10 cm distance with 20 W fluorescent bulb at 30° C. After 80 min reaction, reaction was stopped by heating at 95° C., and produced biotin was determined by the microbiological assay 1 ) using Lactobacillis plantarum. (ATCC8014)
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][C:9]([NH:12][C:13](=[O:17])[NH:14][CH2:15][CH3:16])=[N:8][C:7]=2[CH:6]=[C:5]([C:18]2[CH:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH:4]=1)#[N:2].Cl.[NH2:37]O.[C:39](Cl)(=[O:41])[CH3:40]>N1C=CC=CC=1.CCOC(C)=O>[CH2:15]([NH:14][C:13]([NH:12][C:9]1[S:10][C:11]2[C:3]([C:1]3[N:37]=[C:39]([CH3:40])[O:41][N:2]=3)=[CH:4][C:5]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:35])([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]4)=[N:20][CH:19]=3)=[CH:6][C:7]=2[N:8]=1)=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: NO
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C#N)c2s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-c3noc(C)n3)c2s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
Ethyl 1-[5-[7-cyano-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (327 mg, 0.66 mmol) and hydroxylamine hydrochloride (230 mg, 3.31 mmol) were suspended in pyridine (20 mL) and the mixture stirred at 80° C. for 4 h. The reaction was cooled to rt and acetyl chloride (565 μL, 7.95 mmol) was added then stirred at 80° C. for 9 h. The reaction was diluted with EtOAc (100 mL), washed with dilute HCl (2×100 mL), brine and separated. The organic fraction was dried (Na2SO4) and concentrated under reduced pressure and the oily residue purified by flash column chromatography (40 g GraceResolv silica cartridge—dry loaded), eluting with 50-100% EtOAc/heptane to afford the desired compound (192 mg, 53%) as a white solid. MS: 551.13 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][C:19]=1[C:26]([F:29])([F:28])[F:27]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:14][C:13]([S:15][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:20]=4)=[N:12][N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccc(CCl)cc1C(F)(F)F
Reactant: Sc1nnc(-c2ccc3occc3c2)o1
Product: COc1ccc(CSc2nnc(-c3ccc4occc4c3)o2)cc1C(F)(F)F
Yield: 100 %

Procedure:
In the same manner as in Example 1 and using 5-(1-benzofuran-5-yl)-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl chloride instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 100%) was obtained as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-].[Na+].O.O[O:14][S:15]([O-:17])=O.[K+]>CN(C=O)C.CC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:15]([CH3:9])(=[O:17])=[O:14])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=S([O-])OO
Reactant: C[S-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 2,5-dibromopyridine (1.0 g, 4.22 mmol) in DMF (15 mL) was treated with sodium thiomethoxide (0.69 g, 95%, 9.29 mmol) at ambient temperature. The reaction mixture was stirred for 30 minutes, was diluted water and then extracted with ether. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give crude sulfide as a colorless oil. The crude sulfide was dissolved in acetone (120 mL) and was treated with water (50 mL) followed by Oxone® (7.80 g, 12.7 mmol). The reaction mixture was stirred at ambient temperature for 2 h. After more water was added, the mixture was extracted with ether (200 mL) and EtOAc (150 mL). The organic layers were combined and washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a 0 to 45% EtOAc:hexane gradient to give 0.54 g (54% from 2,5-dibromopyridine) of 5-bromo-2-(methylsulfonyl)pyridine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.78 (d, 1H, J=2.2 Hz), 8.10 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 7.98 (d, 1H, J=8.3 Hz), 3.22 (s, 3H); LRMS (ESI), m/z 236/238 (M+H).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9](C)=[CH:8][C:7](Br)=[CH:6][C:5]=1[CH2:12][Br:13].[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.[C:28]([O-])([O-])=[O:29].[K+].[K+]>C1(C)C=CC=CC=1>[Br:13][CH:12]1[C:5]2[C:4](=[C:9]([O:29][CH3:28])[CH:8]=[CH:7][CH:6]=2)[C:3](=[O:14])[N:23]1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:26])([F:27])[F:15])=[CH:19][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1cccc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2Br
Yield: 65.9 %

Procedure:
4-Bromo-2-bromomethyl-6-methylbenzoic acid methyl ester (762 mg, 2.37 mmol), 4-trifluoromethoxy benzylamine (0.543 mL, 3.56 mmol) and K2CO3 (981 mg, 7.10 mmol) were stirred in toluene (10 mL) at 95° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc/Hexanes) to afford a yellow oil (650 mg, 66%). 1H NMR (300 MHz, CDCl3): δ 7.33-7.36 (m, 2H), 7.18 (d, 2H), 7.13 (s, 1H), 7.07 (s, 1H), 4.75 (s, 2H), 4.22 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(OCC)(=O)C>CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][O:12][C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:6][CH:5]=1
Reactant: Clc1ncccn1
Reactant: CCCCC(CO)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCCCC(COc1ncccn1)(Cn1cncn1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 102.8 %

Procedure:
To a flask was charged 0.15 g (0.0034 mole) of 60% sodium hydride, washed with 2×30 mL hexane, in 20 mL of tetrahydrofuran. While stirring at room temperature, 1.0 g (0.0034 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1yl)methyl]hexan-1-ol was added. The slurry was stirred at room temperature and 0.39 g of 2-chloropyrimidine (0.0034 mole) was added. The reaction was stirred overnight after which TLC using ethyl acetate indicated the reaction was complete. The product was isolated from ether after quenching and washing with water. After drying and removal of the solvent, 1.30 g (100% yield) of an oil resulted.