Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].O/N=C(\N)/C>CN(C=O)C.O>[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28]1[O:29][N:15]=[C:10]([CH3:11])[N:9]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(Cl)c5)nn34)ccnc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C/C(N)=N/O
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(-c6nc(C)no6)c(Cl)c5)nn34)ccnc2c1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
HATU (0.370 g, 0.974 mmol) and 2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.300 g, 0.650 mmol) were taken up in DMF (5 mL). Added Hunig'sBase (0.339 ml, 1.95 mmol). Stirred for 10 min. Added (Z)-N′-hydroxyacetamidine (0.289 g, 3.90 mmol). Stirred for an additional 30 min. Removed DMF in vacuo. Suspended in water. Isolated product by filtration. The resulting solid was allowed to try under vacuum. Split into 3 portions and separately took up in dioxane (4 mL) in a microwave tube and heated for 12 min at 150° C. Combined all 3 reactions. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=500.0 [M+1]+. Calc'd for C25H18ClN7O3: 499.1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[O:16])(C)(C)C.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[NH2:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]2=[O:16]
Reactant: CC(C)(C)OC(=O)NC1CC2CCC1CC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CC2CCC1CC2=O
Temperature: 25 °C
Yield: 91.5 %

Procedure:
(5-Oxo-bicyclo[2.2.2]oct-2-yl)-carbamic acid tert-butyl ester (Preparation 75, 279 g, 1.17 mol, 10 eq) was taken up in DCM (450 mL). TFA (416 mL, 5.60 mol, 4.8 eq) was added dropwise. On addition, the reaction warms to reflux while much gas evolves. The reaction mixture was kept at reflux temperature for 1 hour after which it was allowed to cool to room temperature overnight. The mixture was concentrated and the residue was taken up in DCM (50 mL) and then tert-butyl methyl ether (1.3 L) was added which resulted in a brown suspension. The solids were collected by filtration (P3) and were washed with tert-butyl methyl ether. The latter was dried in vacuo (40° C.) to furnish title compound as an off-white solid (272 g, 1.07 mol, 92%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: C1COCCN1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCOCC3)sc2Br)s1
Reaction time: 3 h
Yield: 77 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (136 mg; 0.33 mmol; 1 eq), is dissolved in DCM (10 ml). Morpholine (0.25 ml; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added under a nitrogen atmosphere. After 3 hours, solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is purified by flash chromatography using cyclohexane/EtOAc (1/1) as eluent, affording the expected compound as an oil (118 mg; 77%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:34])([CH3:33])[CH3:32]>O1CCCC1.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:44]2[CH2:45][CH2:46][N:41]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=3[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:42][CH2:43]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a stirred solution of 4-(benzyloxy)benzoic acid (913 mg) and N,N-dimethylformamide (0.01 mL) in tetrahydrofuran (30 mL) was added oxalyl chloride (0.508 mL) at room temperature. After 1 h the reaction mixture was concentrated under reduced pressure to provide the residue and the residue was dissolved in tetrahydrofuran (30 mL). A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (1.0 g) and triethylamine (1.67 mL) was added to the solution and stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, ethyl acetate) to provide the title compound (1360 mg, 79%) as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)nc1
Product: Cc1c2n(c3c(-c4ccc(Cl)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (62 mg, 75%), MS (ISP) m/z=314.5 [(M+H)+], mp 232° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-chloro-pyridin-3-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH:10]=[CH:9]3)=[CH:4][N:3]=1>[Pt]=O.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH2:10][CH2:9]3)=[CH:4][N:3]=1
Reactant: Brc1ccc(C23C=CCN(CC2)C3)cn1
Agent: O=[Pt]
Solvent: CO
Product: Brc1ccc(C23CCCN(CC2)C3)cn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71.3 %

Procedure:
1.95 g (7.354 mmol) of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (WO 03/057 697) are introduced into 40 ml of methanol in a hydrogenation flask, and 195 mg of platinum oxide are then placed in suspension. The medium is stirred at room temperature under a hydrogen pressure of 26 psi for 45 minutes. The reaction medium is filtered through diatomaceous earth and the solvent is removed by evaporation under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a mixture of chloroform, methanol and aqueous ammonia in 95/5/0.5 proportions. 1.4 g of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]octane are obtained in the form of a waxy oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1.[CH2:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1)[CH3:18].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=1[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][CH:3]=1)[CH3:18]
Reactant: Brc1ccc2cnn(C3CCCCO3)c2c1
Reactant: CCc1cc(OC)c(F)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(OC)c(F)cc1-c1ccc2cnn(C3CCCCO3)c2c1
Temperature: 110 °C
Yield: 71.4 %

Procedure:
To a solution of 6-bromo-1-(tetrahydro-pyran-2-yl)-1H-indazole (WO 2010/027500, 2.25 g, 8.0 mmol) and 2-(2-ethyl-5-fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 13, 2.24 g, 8.0 mmol) in dioxane (32 mL) was added potassium phosphate (5.1 g, 24 mmol) as a solution in water (8 mL). The reaction mixture was degassed with nitrogen and treated with tetrakis (triphenylphosphine) palladium(0) (1.85 g, 1.6 mmol). The reaction mixture was heated at 110° C. for 18 hours, cooled to room temperature and filtered through a pad of Arbocel®, washing with EtOAc (2×100 mL). The filtrate was washed with water (100 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by column chromatography on silica gel eluting with 10% EtOAc in heptane to give the title compound as a white solid (2.024 g) in a 71% yield.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])(=[O:33])=[O:34])[CH:29]=[CH:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1cccc(Br)c1
Product: CN(C)CCNS(=O)(=O)c1cccc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (340 mg, 1.0 mmol) and 3-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.35) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 59%). MS (ISP) 564.3 [(M+H)+]; mp 160–162° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[NH:13][C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8].I[CH3:25]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[F:23])[C:7]([C:9]1[CH:18]=[C:17]([CH3:19])[C:12]2[N:13]([CH3:25])[C:14](=[O:16])[O:15][C:11]=2[CH:10]=1)=[O:8]
Reactant: CI
Reactant: Cc1cc(C(=O)c2ccc(F)c(Br)c2)cc2oc(=O)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)c2ccc(F)c(Br)c2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.175 g (4.00 mmol) sodium hydride (55%, suspension in mineral oil) were added at RT to 1.33 g (3.80 mmol) 6-(3-bromo-4-fluoro-benzoyl)-4-methyl-3H-benzoxazol-2-one in 5 mL DMF. The reaction mixture was stirred for 30 min at RT. Then 0.317 mL (5.00 mmol) iodomethane were added and the mixture was stirred for 1 h at RT. Then 0.100 mL (15.8 mmol) iodomethane were added and the mixture was stirred overnight at RT. After the addition of ice water the reaction mixture was extracted with EtOAc. The organic phase was washed with water, dried on sodium sulphate and evaporated down i. vac. The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated down and dried i. vac.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][N:16]=[N:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[N:15]1[CH:14]=[CH:13][C:18]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH2:1])=[CH:4][CH:5]=2)=[CH:17][N:16]=1
Reactant: Brc1ccnnc1
Reactant: NCc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: NCc1ccc(-c2ccnnc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a sealed tube was added 4-(aminomethyl)phenylboronic acid 1-1 (1.87 g, 10 mmol), 4-bromopyridazine 1-2 (1.58 g, 10 mmol), Pd(PPh3)4 (230 mg, 0.2 mmol), saturated Na2CO3 (15 mL), ethanol (15 mL) and toluene (45 mL). The reaction was heated to 110° C. and stirred for 2 hours. The reaction was cooled down to room temperature. The solvent was removed by rotary evaporation. The residue was dissolved in 10% methanol in DCM. The salt was removed by filtration. The filtrate was dried. The crude product was purified by silica-gel flash chromatography, eluted with 10% methanol in DCM to give (4-(pyridazin-4-yl)phenyl)methanamine 1-3 as off-white solid. MS m/z 186.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15]1.N1CCCCC1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=[O:13])[CH:12]=[CH:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(OC)c(C(=O)C=Cc2c[nH]c3ccccc23)c1
Yield: 44 %

Procedure:
2',5'-Dimethoxyacetophenone (1.80 g) and indole-3-carboxaldehyde (1.45 g) were dissolved in ethanol (20 ml), and piperidine (0.85 g) was added thereto, followed by heating under reflux for 72 hours. The precipitated crystals were collected by filtration, and the obtained crude crystals were recrystallized from ethanol to give Compound 89 (1.35 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47]C(=O)OC(C)(C)C)[CH2:42]2)=[C:34]2[S:40][CH:39]=[CH:38][C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH2:47])[CH2:42]2)=[C:34]2[S:40][CH:39]=[CH:38][C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccsc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccsc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[6-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[3,2-b]pyridin-7-yl]piperidin-3-yl}carbamate (78.5 mg, 0.114 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (28.5 mg, 51%). LCMS calc. for C22H21F2N6OS2 (M+H)+: m/z=487.1. found 487.1. 1H NMR (500 MHz, DMSO-d6) δ 9.56 (s, 1H), 7.95 (d, J=5.5 Hz, 1H), 7.66 (s, 2H), 7.57-7.50 (m, 1H), 7.49 (d, J=5.5 Hz, 1H), 7.28 (t, J=8.8 Hz, 2H), 3.24-3.16 (m, 1H), 3.08-3.01 (m, 1H), 3.01-2.91 (m, 2H), 2.83-2.74 (m, 1H), 1.90-1.67 (m, 3H), 1.24-1.10 (m, 1H) ppm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:21][C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=3)[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COC(=O)c1ccc(CBr)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CN2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a suspension of 4-(4-pyridyl)piperazine (13.1 g) in ethyl acetate (200 ml) was added triethylamine (56 ml) followed dropwise, over 5 hours, by a solution of methyl 4-bromomethylbenzoate (18.41 g). The mixture was stirred at room temperature for 18 hours. The mixture was partitioned between water and ethyl acetate. The organic extracts were dried (MgSO4) and evaporated to give a gum, which was purified by column chromatograhy on silica eluting with increasing concentrations of methanol/dichloromethane to give methyl 4-(4-(4-pyridyl)piperazin-1-ylmethyl)benzoate (13.1 g) as a solid;
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([NH:23][CH2:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[O:15])=[CH:4][N:3]=1
Reactant: NCC1CCOCC1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Product: Cc1cccc2c(Cl)ncc(C(=O)NCC3CCOCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and (tetrahydro-2H-pyran-4-yl)methanamine by following the similar procedure as described for Intermediate-11a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[N:16]=[N:17][S:18][C:19]=2[CH2:20][OH:21])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:21][CH2:20][C:19]1[S:18][N:17]=[N:16][C:15]=1[C:10]1[N:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)[C:13](=[O:14])[O:12][N:11]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1onc(-c2nnsc2CO)n1-c1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)OCc1snnc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[5-(hydroxymethyl)-1,2,3-thiadiazol-4-yl]-1,2,4-oxadiazol-5(4H)-one was dissolved in anhydrous DCM (2 mL) followed by addition of TEA (26 μL, 0.19 mmol). The reaction was stirred at 0° C. for 15 minutes. Methanesulfonyl chloride (13 μL, 0.17 mmol) was added drop-wise and stirred for 15 minutes at 0° C. The reaction was concentrated in vacuo and the crude purified by flash chromatography to give the desired product (42 mg, 65%). 1H NMR (400 MHz, CDCl3): δ 7.50 (m, 1H), 7.25 (m, 2H), 5.83 (s, 2H), 3.20 (s, 3H). MF═C12H8ClFN4O5S2; LCMS calculated for C12H9ClFN4O5S2 (M+H)+: m/z=406.9.
Reaction SMILES: O[C:2]1([C:17]2[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]1=[O:16].OC1(C2C(O)=CC3OCOC=3C=2)C2C(=NC=CC=2)N(CCCCC)C1=O>>[OH:26][C:25]1[C:17]([CH:2]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:5]3[N:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]2=[O:16])=[CH:18][C:19]2[O:23][CH2:22][O:21][C:20]=2[CH:24]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2ncccc21
Agent: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cccnc21
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ncccc21

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations using 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one to replace 3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one, the title compound was obtained (50%): MS (ES+) m/z 341.1 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][C:4](=[O:13])[C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].[Br:22]N1C(=O)CCC1=O>CN(C=O)C.[NH4+].[Cl-]>[Br:22][C:11]1[CH:10]=[CH:9][C:7]2[NH:8][C@@H:2]([CH3:1])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4](=[O:13])[NH:5][C:6]=2[CH:12]=1
Reactant: C[C@@H]1Nc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@@H]1Nc2ccc(Br)cc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 95.7 %

Procedure:
To a 0° C. solution of tert-butyl(2S,3S)-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (107.0 mg, 367 μmol) in DMF (2.45 ml) was added a solution of N-bromosuccinimide (68.6 mg, 386 μmol) in DMF (1.22 ml), dropwise over 5 min. The reaction was stirred at 0° C. for 30 min, then diluted with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layers were washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(2S,3S)-7-bromo-2-methyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamate (130 mg, 96%) as a white solid. MS m/z 392/394 (MNa)+.
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][N:10]2[CH3:11])[CH:6]=[CH:5][CH:4]=1>>[CH3:11][N@@+:10]1([O-:1])[C@H:9]([C:7]2[CH:6]=[CH:5][CH:4]=[N:3][CH:8]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CN1CCCC1c1cccnc1
Reactant: OO
Product: C[N@+]1([O-])CCC[C@H]1c1cccnc1

Procedure:
After a total reaction period of 5 hours, a nicotine conversion of 98% is obtained; the residual hydrogen peroxide content is 1.5%. The resulting oily solution of the oxidation products has a yellowish color and exhibits no odor of nicotine.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:15]3[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH3:21][N:17]1[C:18]2[C:14](=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=3)=[CH:20][CH:19]=2)[C:15]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[C:16]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC(=O)OC)cc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCc1c(-c2ccccc2)n(C)c2ccc(-c3ccc(OCC(=O)O)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-methyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetic acid methyl ester (0.184 g, 0.417 mmol) was reacted with 1N KOH (1.0 ml) in THF/MeOH (3 ml/2 ml) to give the product (0.104 g, 0.243 mmol, 58%) as a white solid, mp 146-148° C. 1H NMR (DMSO-d6) δ 0.73 (t, J=6.8 Hz, 3H), 1.10-1.19 (m, 4H), 1.47-1.54 (m, 2H), 2.62 (t, J=7.4 Hz, 2H), 3.52 (s, 3H), 4.66 (s, 2H), 6.96 (d, J=8.9 Hz, 2H), 7.37-7.46 (m, 5H), 7.51 (t, J=7.0 Hz, 2H), 7.57 (d, J=8.9 Hz, 2H), 7.69 (d, J=1.1 Hz, 1H), 12.96 (broad s, 1H); IR (solid) 3040, 2920, 2860, 1730, 1705, 1605, 1520, 1480, 1430, 1370, and 1230 cm−1; [ESI(−)], m/z 427 (M−H)−; Anal. Calcd. for C28H29NO3.0.25H2O: C, 77.84; H, 6.77; N, 3.24; Found: C, 78.13; H, 6.60; N, 3.19.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[CH:6]([CH3:17])[CH2:5][O:4][CH2:3]1>C(O)C.[Pd]>[CH3:1][CH:2]1[N:7]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[NH2:14])[CH:6]([CH3:17])[CH2:5][O:4][CH2:3]1
Reactant: CC1COCC(C)N1c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC1COCC(C)N1c1cccc(N)c1

Procedure:
Meta-(3,5dimethylmorphohno) nitrobenzene (1a) (2 g, 8.5 mmol) is hydrogenated in ethanol (50 ml), over 10%Pd on carbon (200 mg) for 1.5 hours. The catalyst is removed by filtration and the solvent removed evaporation to yield an oil. The enantiomers can be separated by silica column chromatography. ES+ (M+1) 207.36.