Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][S:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Sc1ccccc1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CSc2ccccc2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and benzenethiol. m/e+ 345 for C22H21N2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.54 (d, J=9.1 Hz, 1H), 7.35 (d, J=1.8 Hz, 2H), 7.32 (m, 5H), 7.07 (d, J=9.1 Hz, 1H), 4.54 (s, 2H), 2.39 (s, 3H), 2.34 (s, 3H) ppm.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 70 °C
Yield: 61.7 %

Procedure:
A mixture of Intermediate 148e (313 mg, 0.7 mmol), Intermediate 186b (262 mg, 0.7 mmol) and DIPEA (182 μL, 1.05 mmol) in dioxane (4 mL) was heated at 70° C. for 20 h. The reaction mixture was cooled to RT and eluted directly on SCX-2 using MeOH and 2M NH3 in MeOH. The basic fractions were evaporated under reduced pressure. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound as a yellow glass (293 mg). LCMS (Method 3): Rt 3.63 min, m/z 679 [MH+].
Reaction SMILES: [CH3:1][C:2]([S-:5])([CH3:4])[CH3:3].[Na+].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>O1CCCC1.ClCCl>[CH3:7][S:8](=[O:10])([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:9]
Reactant: CC(C)(C)[S-]
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)SS(C)(=O)=O
Temperature: -60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Tetrahydrofuran (100 ml) was added to sodium 2-methyl-2-propanethiolate (7.83 g, 69.8 mmol), and the mixture was cooled to −60° C. or lower. A solution of methanesulfonyl chloride (6.77 ml, 87.0 mmol) in tetrahydrofuran (50 ml) was added dropwise to this suspension over 25 minutes. The reaction solution was gradually warmed to room temperature over 2 hours and stirred at room temperature for additional 1 hour. The reaction solution was diluted with dichloromethane (300 ml) and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford S-tert-butyl methanesulfonothioate (Compound SP684) (11.17 g, 76%). The obtained compound was confirmed based on the compound data described in Non patent literature (Inorganic Chemistry, 2010, 49, 8637-8644).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:26][C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]=[O:33]>O1CCCC1>[Cl:26][C:27]1[N:28]=[C:29]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=2)[CH3:35])[S:30][C:31]=1[CH:32]([C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1)[OH:33]
Reactant: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2sc(N(C)Cc3ccc(Cl)cc3)nc2Cl)c2cccnc21
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at −20° C., isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was; allowed to warm to 0° C. in 10 minutes. The reaction mixture was then cooled to −40° C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde (551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to −10° C. in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (552, 0.5 g, 60%). MS (ESI) [M+H+]+=575.29.
Reaction SMILES: N1C=CC=CC=1.C1C([N+]([O-])=[O:14])=CC=C(O)C=1.[CH:17]1([N:23]=[C:24]=[N:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCOCC1>[CH:26]1([NH:25][C:24]([NH:23][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:14])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 3 h

Procedure:
The succinylated 2-azetidinone is dissolved in dioxane (10 ml). Anhydrous pyridine (1 ml) and p-nitrophenol (0.2 g) are added followed by dicyclohexylcarbodiimide (0.6 g, 2.5 mmole). Stirring is continued for 3 hours. The dicyclohexyl-urea formed is filtered and the filtrate is added to controlled pore glass (5 g) suspended in dimethylformamide (5 ml). Triethylamine (2 ml) is added and briefly shaken. After leaving it overnight, the CPG is filtered, washed with methanol, ether and air dried.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:26]=[C:27]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[NH2:28]>>[CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH3:21])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:22]3[O:24][N:28]=[C:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)[N:26]=3)[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Reactant: NC(=NO)c1cccnc1
Product: CCc1ccc(C2CC(c3nc(-c4cccnc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 37 mg (43% of theory)
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>CN(C)C=O>[NH2:24][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38]
Reactant: COC(=O)c1ccccc1OCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCOc3ccccc3C(=O)OC)c2n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound obtained in Example 2-1 step (v) was dissolved in dimethylformamide (50 ml), and potassium carbonate (3.52 g) and methyl 2-(2-bromoethoxy)benzoate (2.2 g) were added thereto. The mixture was stirred at room temperature for 96 hours and partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was dried and concentrated under reduced pressure. The residue was dissolved in methanol and purified by RPHPLC to give the titled compound. Yield: 0.768 g (22%).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:6]1)[CH3:4].Cl[C:22]1[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=2[N:23]=1.O>CN(C=O)C>[CH2:3]([N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:22]3[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:25]4[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=4[N:23]=3)=[CH:16][CH:15]=2)=[N:6]1)[CH3:4]
Reactant: CCn1nc(-c2ccc(O)cc2)c2ncccc21
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
NaH (60% in oil, 59 mg) was added portionwise at room temperature to a solution of 4-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (335 mg) in DMF (3.5 mL). After stirring for 30 min, 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (416 mg) was added, and the mixture was heated for 2 h at 150° C. under microwave irradiation. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/AcOEt) and crystallized from hexane/AcOEt to give the title compound (530 mg).
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:21])[CH3:20]
Reactant: CCCCC/C=C\CCCCCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCC/C=C\CCCCCCCCCCOC(C)=O
Yield: 42 %

Procedure:
The obtained (Z)-11-heptadecenol (Formula II, R=CH3) is added to a mixture of 5 ml. of dry pyridine and 3.5 ml of acetic anhydride, and the mixture is stirred at 0° C. for 3 hours. The solution is poured onto ice and extracted with methylene chloride. The extract is washed with water, 3% aqueous sulfuric acid and again with water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled in fine vacuo. 2.25 g (42%) of (Z)-11-heptadecenyl acetate (Formula I, R=CH3) are obtained; this compound is identical with the product obtained in step (A) above.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]([CH2:13][C@@H:14]1[O:18][C:17](=[O:19])[N:16]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([F:29])[CH:21]=2)[CH2:15]1)=[N+:11]=[N-:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:54]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])(=[O:57])[NH:55][NH2:56]>CN(C=O)C>[C:59]([O:58][C:54]([NH:55][NH:56][C:24](=[O:26])[C:23]1[CH:27]=[CH:28][C:20]([N:16]2[CH2:15][C@H:14]([CH2:13][N:10]=[N+:11]=[N-:12])[O:18][C:17]2=[O:19])=[CH:21][C:22]=1[F:29])=[O:57])([CH3:62])([CH3:61])[CH3:60]
Reactant: CC(C)(C)OC(=O)NN
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C(=O)O)c(F)c2)C(=O)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(N2C[C@H](CN=[N+]=[N-])OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
Diisopropylethylamine (4.67 ml, 0.0268 mol) is added to a mixture of 4-(5(R)-Azidomethyl-2-oxo-oxazolidin-3-yl)-2-fluorobenzoic acid (2.50 g, 0.00892 mol) [prepared according to the procedure described in U.S. Pat. No. 6,239,152] and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.73 g, 0.00981 mol) in DMF (30 ml) and stirred for 20 minutes at room temperature. tert-Butyl carbazate (1.30 g, 0.00981 mol) is then added and the mixture stirred at room temperature overnight. The reaction mixture is evaporated under vacuum and the residue diluted with water. The resulting precipitate is filtered and dried under vacuum to give product as a white solid (3.52 g, 99%); 1HNMR (300 MHz, DMSO-d6) δ 1.42 (s, 9H), 3.72-3.76 (m, 2H), 3.81 (dd, J=6.0, 9.3 Hz, 1H), 4.17 (t, J=9.1 Hz, 1H), 4.88-4.96 (m, 1H), 7.43 (dd, J=2.2, 8.8 Hz, 1H), 7.57 (dd, J=2.2, 13.2, 1H), 7.66 (t, J=8.2, 1H), 8.96 (s, 1H), 9.92 (s, 1H); Rf(EtOAc)=0.54; mp 173-5.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([C:11]([OH:13])=[O:12])[NH:2]1.Br[CH:15]([CH3:17])[CH3:16].[OH-].[Na+]>C(O)C>[CH:15]([N:2]1[CH:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)([CH3:17])[CH3:16]
Reactant: O=C(O)C1Cc2ccccc2CN1
Reactant: CC(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)N1Cc2ccccc2CC1C(=O)O
Yield: 88 %

Procedure:
A solution of 1,2,3,4-tetrahydro-3-isoquinoline-carboxylic acid (9 g, 42 mmol), 2-bromopropane (8 ml, 84 mmol) and 1N NaOH (168 mmol) in ethanol (170 ml) was refluxed for 5 hours, then 2-bromopropane (8 ml, 84 mmol) and 1N NaOH (168 ml, 168 mmol) were added and the mixture was refluxed for 5 hours. Ethanol was removed and the aqueous solution was treated with 6N hydrochloric acid to pH=7. Unreacted starting material was recovered by filtration and the solvent was removed under reduced pressure. The crude was dissolved in ethanol, the inorganics salts were filtered off and the organic solution was evaporated under reduced pressure. This procedure was repeated three times yielding 8.1 g (yield 87%) of pure N-isopropyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid which was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.[N:20]1([CH:26]([C:29]#[N:30])[C:27]#[N:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>[Au].C(Cl)Cl>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:27]([NH2:28])[C:26]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[C:29]([NH2:30])[N:15]=2)=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Reactant: N#CC(C#N)N1CCOCC1
Agent: [Au]
Solvent: ClCCl
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1N1CCOCC1
Temperature: 105 °C

Procedure:
75 mg of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide 1-2-4 (0.29 mmol, 1.0 eq.) and 44 mg morpholin-4-ylmalononitrile [0.29 mmol, 1.0 eq.; for preparation see: H. Gold and O. Bayer, Chem. Ber. 94, 2594 (1961)] were suspended in a small amount of DCM and the resulting suspension was evaporated to dryness. The residue was heated for one h at 105° C. The crude product was purified by flash chromatography yielding 86 mg (0.21 mmol, 72%) of analytically pure target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13](=[CH:16][CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:23].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]2([O:23][CH:16]2[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=C1CCN(C(=O)OCc2ccccc2)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1OC12CCN(C(=O)OCc1ccccc1)C2
Yield: 44.8 %

Procedure:
A solution of 3-ethylidenepyrrolidine-1-carboxylic acid benzyl ester (Example A8, 0.65 g, 2.8 mmol) and 3-chloroperoxybenzoic acid (0.86 g, 5 mmol) in dichloromethane (15 mL) is stirred at room temperature for 3 hours. The excess peracid is decomposed by the addition of 10% sodium sulfite. The organic layer is washed with 5% sodium bicarbonate solution, dried over Na2SO4 and evaporated. The residue is purified by column chromatography (1:1 hexanes/ethyl acetate) to afford the title compound (0.310 g). 1H NMR (200 MHz, CDCl3): δ 7.36–7.26 (m, 5H), 5.14 (s, 2H), 3.73–3.55 (m, 3H), 3.34 (d. 1H), 3.20–3.13 (m, 1H), 2.26–2.11 (m, 1H), 1.90–1.62 (m, 1H), 1.33 (d, 3H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1/[CH:17]=[CH:18]/[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20].O>CS(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH:17]1[CH2:4][CH:18]1[C:19]([N:21]([O:23][CH3:24])[CH3:22])=[O:20]
Reactant: CON(C)C(=O)/C=C/c1cc(F)ccc1Br
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CON(C)C(=O)C1CC1c1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 122 mg, 3.05 mmol, Aldrich) was added to a suspension of trimethylsulfoxonium iodide (671 mg, 3.05 mmol, Aldrich) in DMSO (6 mL). The mixture was stirred at 25° C. for 30 min, and (E)-3-(2-bromo-5-fluorophenyl)-N-methoxy-N-methylacrylamide was added as a solution in DMSO (3 mL). The mixture was stirred at 25° C. for 12 h, then transferred to a separatory funnel with H2O (40 mL), and the title compound was extracted using 75% ether/hexane (3×40 mL). The organic layer was dried over sodium sulfate and concentrated. Purification by flash column chromatography (33% EtOAc/hexane) afforded the title compound as a colorless oil. MS m/z: 302 and 304 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]([NH:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)[C:3]([F:6])([F:5])[F:4].[BH4-].[Na+]>CO.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:1][C@@H:2]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)[C:3]([F:5])([F:6])[F:4]
Reactant: C[C@@H](NCc1ccc(C#N)cc1)C(F)(F)F
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H](NCc1ccc(CN)cc1)C(F)(F)F
Yield: 56.6 %

Procedure:
Add cobalt(II) chloride hexahydrate (1.45 g, 6.09 mmol) to a solution of (R)-4-[(1-methyl-2,2,2-trifluoro-ethylamino)-methyl]-benzonitrile (695 mg, 3.045 mmol) in methanol (20 mL). Add sodium borohydride (1.15 g, 30.45 mmol) in small batches and stir at room temperature for 3 h. Quench with water, add chloroform and filter the mixture through Celite®. Separate layers and extract the aqueous phase twice with chloroform. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (40 g) eluting with a gradient of DCM to 19:1 and 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as an oil (0.4 g, 57%). MS (ES+) m/z: 233 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:28](=[O:29])[O:30][CH3:31])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: COC(=O)Cl
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 3 h

Procedure:
To a solution of 9.24 g of 3-methyl-6-[3-(amino)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 7.9 ml of N,N-diisopropylethylamine followed by 3.5 ml of methyl chloroformate. This mixture was stirred for 3 hours, then the solid was collected and washed with 100 ml of dichloromethane. The solid was heated with dichloromethane-hexane and filtered, giving 8.25 g of the desired product as crystals, mp 150°-153° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:8][NH:9][CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(Br)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(OC2CNC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a solution of tert-butyl 3-(4-bromophenoxy)azetidine-1-carboxylate (300 mg, 0.90 mmol) in CH2Cl2 (5 mL) was added TFA (5 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give 3-(4-bromophenoxy)azetidine (207 mg, 100%) as a yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH3:35][CH:36]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH:44]([CH3:46])[CH3:45])[C:39]=1[NH:47][C:48](=[O:56])[CH2:49][P:50](=O)([O-:54])[O:51][CH2:52][CH3:53])[CH3:37]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:45][CH:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH:36]([CH3:35])[CH3:37])[C:39]=1[NH:47][C:48](=[O:56])[CH2:49][P:50]([NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:54])[O:51][CH2:52][CH3:53])[CH3:46]
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)([O-])CC(=O)Nc1c(C(C)C)cccc1C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CC(=O)Nc1c(C(C)C)cccc1C(C)C)NCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
To a solution of 2,2-diphenylethylamine (0.45 g, 2.3 mmol) and triethylamine (0.35 mL, 2.5 mmol) in methylene chloride (10 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.48 g, 2.5 mmol), followed by (±)-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]phosphonic acid, ethyl ester (Example 5) (0.74 g, 2.3 mmol). 4-Dimethylaminopyridine (DMAP) (0.1 g) is added and the solution is stirred for 48 hours at room temperature. Additional portions of triethylamine (0.1 mL) and EDCI (0.1 g) are added and stirring is continued for another 24 hours. The reaction mixture is diluted with methylene chloride, washed with water, brine, dried over magnesium sulfate, and concentrated. Flash chromatography (ethyl acetate) affords 0.22 g of the product as a white solid. Recrystallization from ethyl acetate/hexane affords 0.18 g of the title compound as a white solid; mp 172°-176° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>C(O)C.O>[C:5]1([C:3]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Nc1ccccn1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cn3ccccc3n2)cc1
Yield: 79 %

Procedure:
Stir a solution of 2-bromoacetophenone (1 g, 5.024 mmol) and 2-aminopyridine (591 mg, 6.280 mmol) in ethanol (4 mL) containing NaHCO3 (658 mg, 7.837 mmol) at room temperature for 6 hours. Dilute the mixture with water (15 mL) and extract with ether (3×20 mL). Wash the combined organic layers with saturated aqueous sodium chloride (25 mL), dry (MgSO4) and concentrate in vacuo. Purify the residue by flash chromatography (SiO2; eluent:hexane/EtOAc 4:1) to give a white solid, 79% yield. MS(ES+): m/z=195.1 (M+H)+