Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:10]([CH:24]=1)[CH2:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](O)=[O:17].[CH:31]1[CH:36]=[N:35][C:34]2N(O)N=N[C:33]=2[CH:32]=1.N1CCCCC1.C(O)C(N)(CO)CO>CN(C=O)C>[CH3:30][O:29][C:27](=[O:28])[CH2:26][O:25][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:24][C:10]=1[CH2:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH:15]([CH3:19])[C:16](=[O:17])[N:35]1[CH2:36][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: On1nnc2cccnc21
Reactant: COC(=O)COc1ccc(Cl)cc1Cc1ccccc1OC(C)C(=O)O
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: C1CCNCC1
Product: COC(=O)COc1ccc(Cl)cc1Cc1ccccc1OC(C)C(=O)N1CCCCC1
Reaction time: 0.83 h

Procedure:
To a solution of PS-EDC (0.558 g, 1.42 mmol/g, 0.792 mmol) in DMF (2 mL) is added 2-[2-(5-chloro-2-methoxycarbonylmethoxy-benzyl)-phenoxy]-propionic acid (Intermediate B) (150 mg, 0.396 mmol) in DMF (2 mL) and HOAT (80.8 mg, 0.594 mmol) in DMF (2 mL). The reaction mixture is agitated for 50 minutes and then treated with piperidine (39.2 μL, 0.396 mmol) and agitated at RT for 2 days. Polymer supported trisamine (0.475 g, 1.42 mmol/g, 1.98 mmol) is then added and the mixture is further agitated overnight. The reaction mixture is filtered to remove the resins and rinsed with methanol and DCM. The filtrate is reduced in vacuo and the crude solid is re-dissolved in DCM and washed with water. The organic portion is separated using a phase separator and concentrated in vacuo to yield a solid which is purified by chromatography on silica eluting with EtOAc/iso-hexane (30% increasing to 50% EtOAc) to yield the titled product as a pale yellow oil; MH+=446.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][C:3]=1[O:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.C(O)(=O)C.[CH2:31]([O:33][C:34](=[O:37])[CH:35]=O)[CH3:32].C([BH3-])#N.[Na+]>CO>[CH2:31]([O:33][C:34](=[O:37])[CH2:35][N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]3)[CH2:15][CH2:16]1)[CH3:32]
Reactant: O=c1[nH]ccc2cc(OC3CCNCC3)c(Cl)cc12
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CN1CCC(Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.5 g (5.38 mmol) of 7-Chloro-6-(piperidin-4-yloxy)-2H-isoquinolin-1-one (7, free base) were dissolved in 100 mL of methanol. At room temperature, 1.09 g (10.8 mmol) of triethylamine, 3.23 g (53.8 mmol) of acetic acid, 7.63 g (33.6 mmol) of glyoxylic acid ethyl ester and molecular sieves (4 A) were added, followed by 253.6 mg (4.04 mmol) of sodium cyanoborohydride. After stirring for 2 h at room temperature, the reaction mixture was filtered and the filtrate was evaporated i. vac. The residue was dissolved in dichloromethane and washed with 1 N NaOH and sat. NaCl-solution. The organic layer was dried with MgSO4 and evaporated. The obtained crude product was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:37]([O:42][CH3:43])([O:40][CH3:41])OC>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:24]=[CH:23][C:20]([CH:37]([O:40][CH3:41])[O:42][CH3:43])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(C=O)cc3)n2)cc1Br
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(OC)c1ccc(-c2nc(-c3ccc(OC(C)C)c(Br)c3)no2)cc1
Yield: 96 %

Procedure:
4-(3-(3-bromo-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde (0.551 g, 1.423 mmol), molecular sieve (4A, 8-12 mesh, 130 mg) and p-toluenesulfonic acid monohydrate (0.037 g, 0.195 mmol) were added in trimethyl orthoformate (4 ml, 36.2 mmol) and methanol (6 ml), the reaction mixture was heated at 80° C. for 16 hr. The solution was cooled, the reaction mixture was concentrated to afford grey solid, which was purified via silica gel chromatography (12 g, 20% EtOAc:Heptane) to afford 3-(3-bromo-4-isopropoxyphenyl)-5-(4-(dimethoxymethyl)phenyl)-1,2,4-oxadiazole (0.61 g, 1.366 mmol, 96% yield) as white solid.
Reaction SMILES: [S].[F-:2].[K+].[F:4][C:5]([F:12])([F:11])[C:6](F)=[C:7]([F:9])[F:8].C[S:14](C)=O>>[F:2][C:7]([F:9])([F:8])[C:6]([C:5]([F:12])([F:11])[F:4])=[S:14]
Reactant: [F-]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: CS(C)=O
Agent: [K+]
Agent: [S]
Product: FC(F)(F)C(=S)C(F)(F)F

Procedure:
Into a 500 mL flask as described in Example II was charged 48 g (1.50 mole) of sulfur, 5 g (0.086 mole) anh. KF and 200 mL of dimethyl sulfoxide. Hexafluoropropene (133 g, 0.89 mole) was reacted over a 6 hour period at 55° C. to give 104 g (0.275 mole) of crude hexafluorothioacetone dimer for a 62% conversion and yield.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:9][O:10][C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:3]([NH:8][C:14]2[CH:15]=[N:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Nc1ncncc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Nc2ncncc2Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.5 %

Procedure:
A mixture of 5-bromopyrimidin-4-amine (344 mg, 1.977 mmol), 6-methoxypyridin-3-ylboronic acid (907 mg, 5.93 mmol), N,N-diisopropylethylamine (1.376 mL, 7.91 mmol) and anhydrous copper (II) acetate (539 mg, 2.97 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The solid was filtered off and washed with CH2Cl2. The solvent was removed in vacuo and the residue was purified by silica gel chromatography eluting with 50% EtOAc/hexanes to give 5-bromo-N-(6-methoxypyridin-3-yl)pyrimidin-4-amine (36 mg, 0.128 mmol, 6.48% yield). 1H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H); 8.46 (s, 1H); 8.28 (s, 1H); 7.85 (dd, J=8.77, 2.48 Hz, 1H); 6.98 (s, 1H); 6.80 (d, J=8.92 Hz, 1H); 3.95 (s, 3H). m/z (ESI, +ve ion) 281.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[CH:9]=[C:8]2[CH2:24][CH2:25][N:26]1C(=O)C2C(=CC=CC=2)C1=O)[CH2:2][CH3:3]>CCO.O.NN>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11]([N:10]([Si:14]([CH:21]([CH3:22])[CH3:23])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[CH:9]=[C:8]2[CH2:24][CH2:25][NH2:26])=[CH:12][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2[Si](C(C)C)(C(C)C)C(C)C
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCOc1ccc2c(c1)c(CCN)cn2[Si](C(C)C)(C(C)C)C(C)C

Procedure:
Combine 2-(2-(5-propoxy-1-triisopropylsilanyl-1H-indol-3-yl)ethyl)isoindole-1,3-dione (416 mg, 0.8 mmol) in 20 mL EtOH and 1 mL hydrazine hydrate. Reflux for 3 hours, filter through celite and concentrate to residue. Dissolve the residue in 10 mL MeOH and load onto a 12 g SCX ion exchange cartridge and rinse sequentially with MeOH, DMP, then MeOH. Elute the product with 2 M NH3 in MeOH to give the title compound as an oil: ISMS 375 (M+1); 1H NMR (CDCl3) 7.34–7.32 (d, 1H), 7.02 (s, 1H), 7.00–6.99 (d, 1H), 6.80–6.77 (m, 1H), 3.97–3.94 (m, 2H), 3.01–2.98 (m, 2H), 2.86–2.83 (m, 2H), 1.88–1.76 (m 2H), 1.70–1.58 (m, 3H), 1.3 (bs, 2H), 1.14–1.08 (m, 18H), 1.06–1.02 (t, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:27]=[C:28]([CH3:41])[N:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:30]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[N:27]=[C:28]([CH3:41])[N:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[C:34]([F:40])[CH:33]=4)[CH:30]=3)[CH2:21][C:20]2=[O:42])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: Cc1nc(CN2CCN(c3cccc4ccc(OCc5ccccc5)cc34)C(=O)C2)cn1Cc1ccc(C#N)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc(CN2CCN(c3cccc4ccc(O)cc34)C(=O)C2)cn1Cc1ccc(C#N)c(F)c1
Reaction time: 16 h

Procedure:
To a solution of the benzyl ether from Step B (240 mg, 0.43 mmol) in 4 mL of 1:1 MeOH/EtOAc was added 10% palladium on carbon (240 mg). The solution was stirred under a balloon atmosphere of hydrogen at room temperature. After 16 hours, the solution was filtered through celite. Concentration in vacuo provided the titled which was used in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3](C([O-])=O)[C:4]([O:6][CH3:7])=[O:5].S(Cl)(Cl)=[O:12].[CH2:15]([Cl:17])Cl>>[Cl:17][C:15]([CH2:1][O:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:12]
Reactant: COC(=O)C(OC)C(=O)[O-]
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Product: COC(=O)COCC(=O)Cl

Procedure:
Mono-methyl methoxymalonate (9.8 grams, 0.07 mole), prepared in Example LVI (Compound 214) was reacted with thionyl chloride (15.74 grams, 0.13 mole) in 100 milliliters of methylene chloride in a manner similar to that described in Example LIII Part C, to give 11.06 grams (0.07 mole) of methyl (chlorocarbonyl)methoxyacetate. NMR analysis of the product indicated the following:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.C([Li])(C)(C)C.[CH3:26][C:27]([CH3:29])=[O:28].O>O1CCCC1>[CH:12]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:27]([OH:28])([CH3:29])[CH3:26])[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:14])[CH3:13]
Reactant: CC(C)=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(C)(C)O)cnc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To 5-bromo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (2, 2.0 g, 5.66 mmol, prepared as described in Example 4) in tetrahydrofuran (20.0 mL), cooled in a −78° C. acetone/dry ice bath, under an atmosphere of nitrogen, was added tert-butyllithium (1.7 M in tetrahydrofuran, 7.3 mL, 12 mmol) dropwise. After 20 minutes, acetone (0.830 mL, 11 mmol) was added dropwise to the reaction. The reaction was stirred for 30 minutes at −78° C. and then allowed to reach room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give the compound (9, 1.30 g, 69%). MS (ESI) [M+H+]+=333.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>ClCCl.O>[CH3:30][O:29][C:27](=[O:28])[CH2:26][CH2:25][N:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[CH2:13][O:12][C:11]1[CH:20]=[CH:21][C:8]([O:7][C:6]2[CH:22]=[CH:23][C:3]([Cl:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)CCBr
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCCN3)cc2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCN1CCCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 25 %

Procedure:
A solution of (S)-2-[4-(4-chloro-phenoxy)-phenoxymethyl]-piperidine hydrochloride (218 mg, 0.615 mmol), methyl 3-bromopropionate (128 mg, 0.769 mmol), and triethylamine (124 mg, 1.23 mmol) in dichloromethane (2.5 mL) was heated for 18 h at 30° C. The mixture was diluted with 5 mls of water and extracted with dichloromethane (8 mL). The aqueous layer was re-extracted with ethyl acetate (8 mL). The combined organic layers were dried over anhy. Na2SO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the product (62 mg, 25%): 1H NMR (400 MHz, CDCl3); δ 1.48-1.77 (m, 6H), 2.22-2.36 (m, 1H), 2.52-2.57 (m, 2H), 2.68-2.71 (m, 1H), 2.84-2.97 (m, 2H), 3.09-3.16 (m, 1H), 3.66 (s, 3H), 3.91-3.94 (dd, 1H J1=4.4 Hz, J2=10.0 Hz), 4.02-4.06 (dd, 1H J1=5.2 Hz, J2=10.0 Hz), 6.86-6.96 (m, 5H), 7.23-7.26 (m, 3H)
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.C([Li])CCC.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[C:33]=2[CH:38]=[O:39])=[CH:28][CH:27]=1>C1COCC1>[CH2:1]([C:8]1[CH:13]=[C:12]([CH:38]([C:33]2[C:34]([CH3:37])=[N:35][O:36][C:32]=2[C:29]2[CH:30]=[CH:31][C:26]([Br:25])=[CH:27][CH:28]=2)[OH:39])[CH:11]=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cncc(Cc2ccccc2)c1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cncc(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Benzyl-5-bromo-pyridine (0.474 g, 1.91 mmol) was dissolved in THF (10 mL) and cooled to 0° C. Isopropylmagnesium chloride (2 M in THF, 0.96 mL, 1.91 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 1 hour. Analytical LCMS indicated no reaction so an additional portion of isopropylmagnesium chloride (1.91 mmol) was added and the reaction stirred for 1 hour at room temperature. Analytical LCMS still indicated no progress so the reaction was cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 0.764 mL, 1.91 mL) was added. The reaction was allowed to slowly warm to 0° C. then 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.610 g, 2.29 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was quenched with H2O, submitted to standard aqueous workup and then purified via silica gel chromatography to yield the title compound.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:5]1)#[N:2]>C(O)(=O)C.[Pt](=O)=O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]([CH2:12][C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:5]1
Reactant: CC(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC(C)(C)O1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1

Procedure:
A mixture of (±)-cis-1-methylethyl 6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.55 g, in glacial acetic acid is hydrogenated with platinum dioxide at 50 pounds per square inch (PSI). Concentration, dilution with ethyl acetate and bicarbonate wash, followed by washing with brine and drying provides 250 mg of (±)-cis-1-methylethyl 6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate. MS 260.1, 244.1 200 MHz NMR (CDCl3) δ1.25 (d, 6H, J=7 Hz), 1.32 (m, 1H), 1.36 (s, 3H), 1.45 (s, 3H), 1.60 (m, 1H), 2.33 (dd, 1H, J=15, 6 Hz), 2.49 (dd, 1H, J=15, 6 Hz), 2.85 (br t, 2H, J=6 Hz), 3.40 (br s, 2H), 4.00 (m, 1H), 4.29 (m, 1H), 12.03 (septet, 1H, J=7 Hz).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14]C(=O)OCC2C=CC=CC=2)[CH2:10][CH2:9]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].Cl>ClCCl>[CH2:25]([S:27]([N:8]1[CH2:9][CH2:10][CH:11]([NH2:14])[CH2:12][CH2:13]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(NC1CCNCC1)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (10 mL) was added to a dichloromethane (90 mL) solution of Benzyl piperidin-4-ylcarbamate (5.09 g) at 0° C. followed by the dropwise addition of ethane sulfonylchloride (which may be referred to as sso10; 3.2 mL; TCI) and the resulting mixture was stirred overnight slowly raising to room temperature. 1 N Hydrochloric acid (90 mL; WAKO) was added to the reaction mixture solution, the resulting mixture was stirred for approx. 10 minutes, then the reaction mixture was extracted with chloroform, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Yamazen; chloroform/methanol). Palladium hydroxide (20% by weight, Wet-type, 5 g; NECHEM) was added to a methanol (90 mL) solution of this product under a nitrogen atmosphere. The atmosphere in a reaction vessel was replaced with hydrogen at room temperature, the resulting mixture was stirred overnight, the atmosphere in the reaction vessel was returned to a nitrogen atmosphere, the residue was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dried to give the title compound (3.32 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[CH3:14])[C:5]([NH:7][CH:8]1[CH2:10][CH2:9]1)=[O:6].[F:15][C:16]1[CH:17]=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH:24]=1)[C:21](O)=[O:22]>>[F:15][C:16]1[CH:17]=[CH:18][C:19]([N+:25]([O-:27])=[O:26])=[C:20]([CH:24]=1)[C:21]([NH:1][C:2]1[CH:3]=[C:4]([C:5]([NH:7][CH:8]2[CH2:9][CH2:10]2)=[O:6])[CH:11]=[CH:12][C:13]=1[CH3:14])=[O:22]
Reactant: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
Using an analogous procedure to that described paragraph (A) in the portion of Example 1 which is concerned with the preparation of starting materials, 3-amino-N-cyclopropyl-4-methylbenzamide was reacted with 5-fluoro-2-nitrobenzoic acid to give 5-fluoro-N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.30 (s, 3H), 2.85 (m, 1H), 7.31 (m, 1H), 7.61 (m, 2H), 7.76 (m, 1H), 7.94 (s, 1H), 8.26 (m, 1H), 8.40 (m, 1H), 10.25 (s, 1H); Mass Spectrum: M−H+ 356.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](Br)[CH:9]=1)(=[O:5])=[O:4].CCO.[C:19]1(B(O)O)[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCOC(C)=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>[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[CH:9]=1)(=[O:5])=[O:4]
Reactant: OB(O)C1=CCCCC1
Reactant: CNS(=O)(=O)CCc1ccc(N)c(Br)c1
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
Solvent: CCOC(C)=O
Product: CNS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Temperature: 80 °C
Yield: 69.2 %

Procedure:
A solution of 177 mg (0.604 mmol) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid methylamide (as prepared in the previous step) in toluene (5 mL) and EtOH (2.5 mL) was treated with 83.7 mg (0.664 mmol) of cyclohex-1-enylboronic acid and 2.40 mL (4.83 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 67.3 mg (0.0604 mmol) of Pd(PPh3)4, and heated to 80° C. for 19 h. The mixture was diluted with EtOAc (15 mL) and washed with water (1×10 mL). The aqueous layer was extracted with EtOAc (1×10 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 25-g Varian MegaBond Elut SPE column with 50% EtOAc-hexane afforded 123 mg (69%) of the title compound as a white solid: 1H-NMR (CD3CN; 400 MHz): δ 6.90 (dd, 1H, J=8.0, 2.0 Hz), 6.83 (d, 1H, J=2.0 Hz), 6.32 (d, 1H, J=8.0 Hz), 5.70-5.66 (m, 1H), 4.97-4.90 (m, 2H), 4.08-3.99 (br s, 2H), 3.24-3.17 (m, 2H), 2.91-2.84 (m, 2H), 2.66 (d, 3H, J=5.2 Hz), 2.24-2.15 (m, 4H), 1.82-1.74 (m, 2H), 1.74-1.66 (m, 2H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].O>CN1CCCC1=O>[CH2:1]([N:15]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(CN(c2ccccc2)c2cccc3ccccc23)cc1
Reaction time: 2 h
Yield: 65 %

Procedure:
Benzyl bromide (0.15M) was added to a stirred mixture of 1-phenylaminonaphthalene (0.1M) and KOH (0.15M) in N-methyl pyrrolidone (70 cm3) at 120° C. After 2 hours further stirring the mixture was poured in to water, the precipitate filtered off, washed and re-crystallised from methanol to give 20 g (65% yield) of a white solid mp 120°-123° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:3]1=2.B.C(OCC)(=O)C>O1CCCC1.O>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1CC2=O
Agent: B
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1Cc2ccccc2Sc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 5.1 gm. of 10,11-dihydro-11-oxodibenzo[b,f]thiepin-3-carboxylic acid in 100 cc. of tetrahydrofuran and add 35 cc. of 1M borane in tetrahydrofuran at room temperature under a nitrogen atmosphere. Stir the mixture at room temperature for 3 hours. Slowly dilute the reaction mixture with water and then with ethyl acetate. Wash with aqueous sodium chloride, dry and evaporate to an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[CH:13]=2)[CH:5]=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30].CN(C(ON1N=[N:47][C:42]2[CH:43]=[CH:44][CH:45]=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][CH2:57][N:58](C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:58][CH2:57][CH2:56][N:47]3[CH2:42][CH2:43][CH2:44][CH2:45]3)=[O:18])=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[CH:13]=2)[CH:5]=[CH:4][C:3]=1[N+:29]([O-:31])=[O:30]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Nc1nc(NCCNc2ccc(C(=O)O)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Nc1nc(NCCNc2ccc(C(=O)NCCN3CCCC3)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]

Procedure:
The amine (1.5–2.0 equivalents) is added to a stirred solution of acid 4 (1.0 eq., 25 mg), HBTU (1.5 eq.), Hünig's base (2.0 eq.) and DMF (0.4 ml). The acid 4 is pre-activated by premixed the acid 4, HBTU, Hünig's base and DMF together sequentially in this order in a vial at room temperature under argon. The reaction is stirred for 3–4 h until complete as shown by LCMS and HPLC. At times, it is necessary to add 0.25 or 0.5 equivalents more of the coupling reagents to complete the reaction. The reaction is purified by preparative HPLC. The entire reaction is injected directly onto the preparative HPLC. The purified fractions are pooled and lyophilized to give the amide 5 as a yellow powder in greater than 85% purity and in yields of 50–70%. Preparation of N-(2-{[3-(2,4-dichlorophenyl)-4-cyanophenyl]amino}ethyl)(tert-butoxy)carboxamide (6).