Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=[N:14]O)[CH2:10][CH2:9]1.C(=O)([O-])[O-:28].[Na+].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:20][C@H:19]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:18][C:17]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C:11](=[O:28])[NH:14][CH2:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=NO)CC3)c(F)c2)C(=O)O1
Reactant: O=C([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCNC(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 0.42 h

Procedure:
A stirred mixture of the compound of product of Step 3 (0.200 g, 0.549 mmol) in acetone (5.3 mL), under nitrogen, is treated first with 5% aqueous sodium carbonate (5.3 mL) and then, dropwise during 3minutes with a solution of p-toluenesulfonyl chloride (0.16 g, 0.82 mmol) in acetone (2.7 mL). Initially this mixture is a two phase solution; however, after about 25minutes a precipitate began to form. It is kept at ambient temperature (23° C.) for 4 hours and filtered. The filtrate is concentrated under reduced pressure to remove acetone and the aqueous residue is extracted with CH2Cl2. The extract is dried (MgSO4) and concentrated to give a small amount of crude product. Most of the product is in the aqueous layer which is concentrated in vacuo. The residue is combined with the crude product from the CH2Cl2 extract and chromatographed on silica gel with mixtures of MeOH--NH4OH--CH2CI2 that continued 3-5% MeOH and 0.3-0.5% NH4OH. The product is crystallized from MeOH--EtOAc to give the title compound. mp 140-146° C.;
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:22])[C:6]=1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH3:23][N:24](C=O)C>C(#N)C>[CH3:22][C:5]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:2]([CH3:1])[NH:3][C:4]=1[C:23]#[N:24]
Reactant: Cc1c[nH]c(C)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Reactant: CN(C)C=O
Solvent: CC#N
Product: Cc1[nH]c(C#N)c(C)c1Cc1ccccc1S(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A mixture of 2,4-dimethyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole (128.0 mg, 0.402 mmol) and N-chlorosulfonylisocyanide (43.7 μl, 0.502 mmol) in acetonitrile (2.0 ml) was stirred at 25° C. for 1 hour. DMF (31.1 μl, 0.402 mmol) was then added and the resulting mixture was stirred for an additional 16 h at room temperature. The reaction was quenched with water (100 ml) and extracted with dichloromethane (100 ml×2). The organic layers were combined, filtered, and evaporated to give an oil. The oil was purified by column chromatography (0 to 50% ethyl acetate in hexanes) to give 3,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole-2-carbonitrile (49.6 mg, 0.144 mmol, 35.9% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].C1C[O:31]CC1.[OH-].[Na+].OO>C(Cl)Cl.O>[OH:31][CH2:2][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][N:17]=2)[CH3:15])=[O:12])=[CH:8][CH:9]=1)[CH3:3]
Reactant: C1CCOC1
Reactant: C=C(C)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(CO)c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A microwave vial was charged with 2-(4-isopropenylphenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide (300 mg, 0.793 mmol) and THF (500 uL). The solution was cooled to 0° C. and borane tetrahydrofuran complex (1.19 mL, 1.19 mmol) was added via syringe. The reaction was warmed to room temperature over 1.5 h., then NaOH (5M, 634 uL, 3.17 mmol) was added dropwise, followed by the slow addition of hydrogen peroxide (30 wt. % in water, 991 uL, 8.72 mmol). After stirring for 30 min, the mixture was diluted with CH2Cl2 (30 mL) and water (30 mL), and the layers were separated. The aqueous layer was washed with CH2Cl2 (2×15 mL) and the combined organic layer was dried over MgSO4, filtered, and concentrated. The resulting crude material was purified by normal phase chromatography (20-100% EtOAc/Hexanes) to give 133 mg (42%) of 2-[4-(2-hydroxy-1-methylethyl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide as a colorless oil. 1H NMR (CDCl3, 400 MHz) 8.20 (d, J=2.57 Hz, 1H), 7.21 (m, 6H), 6.69 (d, J=6.96 Hz, 1H), 5.10 (quint. J=6.96 Hz, 1H), 4.38 (q, J=8.00, 2H), 3.71 (m, 2H), 3.57 (s, 2H), 2.96 (m, 1H), 1.40 (d, J=6.67 Hz, 3H), 1.28 (d, J=6.96 Hz, 3H); MS (Electrospray): m/z 397.4 (M+H). The two diastereomers were separable by chiral HPLC under the following conditions: Column: ChiralPak AD (4.6 mm×250 mm, 10 u), Solvent: Hex/EtOH/MeOH (85/7.5/7.5), 1 mL/L diethylamine, Flow rate: 1 mL/min, Retention times: 11.3 and 12.8 min
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:23])=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[N:5]=C(C1C=CC=CC=1)C1C=CC=CC=1.BrC1C=C(F)C=C(Br)C=1Cl.C(=N)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([Cl:23])=[C:4]([CH:19]=[C:20]([F:22])[CH:21]=1)[NH2:5]
Reactant: Fc1cc(Br)c(Cl)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Fc1cc(Br)c(Cl)c(Br)c1
Solvent: Cc1ccccc1
Product: Nc1cc(F)cc(Br)c1Cl
Temperature: 80 °C

Procedure:
3-bromo-2-chloro-N-(diphenylmethylene)-5-fluoroaniline. A mixture of 2,6-dibromo-4-fluoro-1-chlorobenzene (865 mg, 3 mmol), benzophenone imine (0.61 ml, 3.6 mmol), Pd2(dba)3 (137 mg, 0.15 mmol), sodium t-butoxide (432 mg, 4.5 mmol), (S)-BINAP (280 mg, 0.45 mmol), and toluene (30 ml) was heated at 80° C. for 16 h. The mixture was extracted with ethyl acetate and the combined organic phase washed with brine. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by silica gel flash chromatography (40:1 to 20:1 hexanes/ethyl acetate eluant) to provide the title compound as a powder. MS m/z 388.9 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>O1CCCC1.N1C=CC=CC=1>[CH3:7][C:5]1[O:4][N:3]=[C:2]([NH:1][C:8](=[O:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1
Reactant: Cc1cc(N)no1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)Oc2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
3-Amino-5-methylisoxazole (1.00 g) purchased from Aldrich Co. was dissolved in tetrahydrofuran (20 ml) and pyridine (1.5 ml), and after cooling to 0° C. under a nitrogen atmosphere, phenyl chlorocarbonate (1.4 ml) was added and the mixture was stirred at room temperature for 2 hours. Water was added, extraction was performed twice with ethyl acetate, and then the organic layers were combined, washed with water and saturated brine in that order, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was triturated with diethyl ether and n-hexane to obtain the title compound (1.54 g) (68% yield).
Reaction SMILES: Br[C:2]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.ClCCl.C([O:39][C:40](=[O:56])[CH2:41][N:42]1[CH:46]=[C:45](B2OC(C)(C)C(C)(C)O2)[CH:44]=[N:43]1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.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].O1CCOCC1>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:8]2[N:9]=[C:4]3[CH:3]=[C:2]([C:45]4[CH:44]=[N:43][N:42]([CH2:41][C:40]([OH:56])=[O:39])[CH:46]=4)[N:22]([S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:5]3=[N:6][CH:7]=2)[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(CCc2cnc3c(cc(-c4cnn(CC(=O)O)c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Temperature: 88 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A stirred mixture of 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (from Example 1, Step 4, 40.0 mg, 79.7 μmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (3.25 mg, 3.98 μmol), tert-butyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate (24.5 mg, 79.6 μmol), and potassium phosphate (33.8 mg, 0.159 mmol) in water (0.5 mL)/1,4-dioxane (1.0 mL) was heated at 88° C. After 1 hour, the reaction was quenched with saturated aqueous NH4Cl, extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1 mL) was added at ambient temperature. After 2 hours, the volatiles were removed under vacuum to afford the desired product (40 mg, 92%). LCMS calculated for C27H26N5O6S (M+H)+: m/z=548.2. Found: 548.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].C(O)CC[OH:9].OC(C)C=O>[Ni]>[NH2:1][CH2:2][CH2:3][CH2:4][OH:9].[NH2:1][CH2:2][CH2:3][CH2:4][NH2:5]
Reactant: OCCCO
Agent: [Ni]
Agent: CC(O)C=O
Agent: NCCCN
Product: NCCCO

Procedure:
In the case of the two-step procedure for making 1,3-diaminopropane (Equations II and III), the 3-amino-1-propane (APO) intermediate was first generated in 84% yield under relatively mild hydroamination conditions (120° C., LHSV 0.4) using a supported-nickel catalyst from Engelhard (Ni-1404, T 3/16", 69% nickel, ex. 12). Identification was by gc-ms/ir. Major co-products include 1,3-propanediol (2.5%), 1,3-diaminopropane (1.2-1.6%), plus lights. Hydroxypropanal conversion was essentially quantitative. A subsequent reamination of this 3-amino-1-propanol (APO) intermediate, as an aqueous 25% solution, produced 1,3-diaminopropane in 50% selectivity at 180° C., LHSV 0.4, using the Raney cobalt catalyst, R-2796 (ex. 13). The major co-products of this second stage, higher temperature, amination were DPTA (ca. 29%) and tripropylenetetramine (TPTA, 12%). Again, there was no gc-ms/ir evidence for cyclic (piperazine-type) derivatives and N-propyl-1,3-diaminopropane was the major N-alkylated material. The 1,3-diaminopropane may be isolated from the crude, liquid, polyamine product via atmospheric distillation. Amination of APO over six days generated several hundred grams of crude DAP and its homologues. Ramping the amination temperature slightly (180-185° C.) allowed activity to be maintained and conversion held at about 85%. It may be possible to further limit the extent of DAP homologation, and thereby further raise the DAP selectivity, by lowering the water content of APO feed, raising the LHSV, and providing more ammonia partial pressure.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Li+].Cl>C1COCC1.O>[CH3:1][S:2]([O:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=3[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc(OCCCc2ccc(OCc3ccccc3C(=O)O)cc2)cc1
Yield: 23.8 %

Procedure:
Methyl 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]methyl}benzoate (0.38 g, 0.81 mmol) was dissolved in a mixture of THF/water (7/1, 4 ml) and lithium hydroxide (9.3 mg, 0.39 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 88 mg of 2-{[4-(3-{4-[(methylsulfonyl)oxy]phenoxy}propyl)phenoxy]-methyl}benzoic acid (yield 23.7%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][S:10][C:4]=2[CH:3]=1.O.C(OCC)(=O)C.[CH3:21][N:22](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[O:11]=[C:6]1[C:5]2[CH:12]=[CH:13][C:2]([C:21]#[N:22])=[CH:3][C:4]=2[S:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C1CCCSc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc2c(c1)SCCCC2=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 8-bromo-5-oxo-2,3,4,5-tetrahydro-1-benzothiepine (5.00 g) synthesized according to a known method in N,N-dimethylformamide (50 ml) were added zinc cyanide (2.28 g) and tetrakis(triphenylphosphine)palladium(0) (1.13 g) and the mixture was stirred at 80-90° C. for 1 hr. The reaction mixture was allowed to warm to room temperature and water (500 ml) and ethyl acetate (100 ml) were added. The mixture was passed through celite. The filtrate was extracted with ethyl acetate and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was recrystallized from ethyl acetate and hexane to give the objective 5-oxo-2,3,4,5-tetrahydro-1-benzothiepine-8-carbonitrile (3.37 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:17][C:16]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:14]([Cl:13])[CH:15]=2)=[O:11])=[C:4]([F:12])[CH:3]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Br)cc1F)Nc1ccc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)acetic acid (144 mg, 0.617 mmol), 3,4-dichloroaniline (100 mg, 0.617 mmol) and HATU (704 mg, 1.852 mmol) in DCM (20 mL) was added Et3N (0.258 mL, 1.852 mmol) dropwise. Then the mixture was stirred at 20° C. under a N2 atmosphere for 3 h. After LCMS analysis showed the starting material had disappeared, the solvent was removed in vacuo. Then the crude product was dissolved in DCM and washed with H2O and brine. The organic layer was evaporated to dryness to give the crude product which was purified by silica column chromatography (PE/EA=100/1 to 8/1) to afford pure product 2-(4-bromo-2-fluorophenyl)-N-(3,4-dichlorophenyl)acetamide (190 mg, 0.419 mmol, 67.8% yield): 1H NMR: (400 MHz, CD3OD) δ 10.25 (br. s, 1H), 7.89 (s, 1H), 7.44 (s, 2H), 7.28-7.37 (m, 3H), 3.74 (s, 2H); ES-LCMS: m/z 377.9 (M+H).
Reaction SMILES: [CH3:1][CH:2]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][N:8]=1)[C:3]([O:5][CH3:6])=[O:4].[N+:16]([O-])([OH:18])=[O:17]>>[CH3:1][CH:2]([C:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)C(C)c1nsc2ccccc12
Product: COC(=O)C(C)c1nsc2ccc([N+](=O)[O-])cc12
Reaction time: 8 h

Procedure:
Methyl α-methyl-1,2-benzisothiazole-3-acetate (15.96 g, 72.13 mmol) is added dropwise to nitric acid (90%, 100 mL) while maintaining the reaction mixture temperature below 5° C. The reaction mixture is stirred overnight, poured onto ice and extracted with methylene chloride. The organic extracts are combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an orange oil. Column chromatography of the oil using silica gel and ether/hexanes solutions gives the title product as an orange solid, mp 88°-90° C.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([N:29]=[N+:30]=[N-:31])[CH2:23]2)=[C:15](Cl)[N:14]=1>O>[NH2:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[CH:18][N:19]2[C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([N:29]=[N+:30]=[N-:31])[CH2:23]2)=[C:15]([NH:11][C@@H:9]2[CH2:10][C@H:8]2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:14]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(Cl)nc(N)nc32)O[C@@H]1CO
Agent: Cl
Solvent: O
Product: [N-]=[N+]=N[C@H]1C[C@H](n2cnc3c(N[C@@H]4C[C@H]4c4ccccc4)nc(N)nc32)O[C@@H]1CO
Temperature: 50 °C

Procedure:
Trans-2-phenylcyclopropylamine hydrochloride (Aldrich, lot #01903MK, 2.5 g, 14.7 mmol) was dissolved in 5 mL H2O and the pH adjusted to pH 12. The aqueous solution was extracted with 10 mL EtOAc. The EtOAc was evaporated to dryness and dissolved in 25 mL EtOH. 2-Amino-9-(3-azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-6-chloro-9H-purine (Example 3d) (0.4 g, 1.29 mmol) was added to the ethanolic solution then placed in a sealed tube and heated at 50° C. for 18 hours. The solvents were removed in vacuo to yield a dark oil. The oil was chromatographed on basic alumina eluted with 1% MeOH in CHCl3. The impure product fractions were combined, evaporated, and rechromatographed on silica gel eluted with 5% MeOH in CHCl3. The collected impure product was again applied to basic alumina eluted with 1% MeOH in CHCl3 to give, after combination and evaporation of appropriate fractions, 0.0802 g (0.2 mMol, 15.5%); mp=65°-70°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]([CH2:20][CH2:21][NH2:22])[CH3:19]>CS(C)=O>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][NH:22][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(-c2ccnc(Cl)n2)cc1
Solvent: CS(C)=O
Product: CN(C)CCNc1nccc(-c2ccc(C(=O)O)cc2)n1
Temperature: 85 °C
Reaction time: 3.5 h
Yield: 103.4 %

Procedure:
To a solution of 4-[2-chloro-pyrimidin-4-yl]-benzoic acid (234 mg, 1 mmol, reference example 11 g) in DMSO (2 mL) is added 2-(N,N-dimethyl-amino)ethylamine (291 mL, 2 mmol). The resulting solution is heated to 85° C. and stirred at this temperature for 3.5 hours, then cooled and concentrated. The residue is purified by reverese phase HPLC to give 296 mg of the title compound as a TFA salt. 1H NMR (CD3OD) d 2.97 (s, 6H), 3.45 (t, J=6 Hz, 2H), 3.88 (t, J=6 Hz, 2H), 7.31 (d, J=5 Hz, 1H), 8.13 (d, J=8 Hz, 2H), 8.20 (d, J=8 Hz, 2H), 8.44 (d, J=5 Hz, 1H). MS (ion spray) m/z 286 (M+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])#[CH:15]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CC(C)c1nnc2ccc(C#Cc3ccc(F)cc3F)nn12
Temperature: 60 °C
Yield: 64.1 %

Procedure:
A solution of 6-chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (20.0 g, 102 mmol, Preparation #G.1) in DMF (300 mL) was evacuated and purged with nitrogen 3 times. To the reaction mixture was added 1-ethynyl-2,4-difluorobenzene (21.1 g, 153 mmol), CuI (0.969 g, 5.09 mmol), TEA (42.5 mL, 305 mmol) and bis(triphenylphosphine)palladium(II) chloride (3.57 g, 5.09 mmol). The reaction mixture was evacuated and purged with nitrogen 3 times. The reaction mixture was heated to about 60° C. for about 6 h, cooled to ambient temperature, and diluted with EtOAc (500 mL). The organic solution was washed with water (3×500 mL), brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was dissolved in a minimal amount of hot DCM and allowed to cool to ambient temperature. The solid 1,2-bis(2,4-difluorophenyl)ethyne (6.7 g, 26.3%) was filtered off and the filtrate was purified by silica gel chromatography using heptane/EtOAc (gradient, 1:1 to 0:1) to give product. The product was then precipitated by dissolving in EtOAc (500 mL) and adding heptane (100 mL portions) while concentrating in vacuo. The solid was collected by vacuum filtration and dried under vacuum to give the title compound (19.5 g, 64%) as an off white solid. LC/MS (Table 1, Method a) Rt=2.72 min; MS m/z: 299.1 (M+H)+.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(OCC)(=O)C>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:9][CH:10]=1
Reactant: NCCN1CCOCC1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCN3CCOCC3)ncc2Cl)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
A 1,4-dioxane (1.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (100 mg, 0.24 mmol) obtained in Example 54 and 4-(2-aminoethyl)morpholine (200 μl) was stirred at 100° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and brine, dried and concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel chromatography (3% methanol/chloroform) to give the title compound (12 mg, 10%) as an oil.