Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([N+:15]([O-])=O)=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2].[H][H]>CCO.[Pd]>[CH2:1]([N:3]1[CH2:13][CH:12]2[CH2:14][CH:5]([C:6]3[C:11]2=[CH:10][C:9]([NH2:15])=[CH:8][CH:7]=3)[CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Product: CCN1CC2CC(C1)c1cc(N)ccc12
Yield: 98.5 %

Procedure:
10-ethyl-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (280 mg, 1.20 mmol) in 10 ml EtOH in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-ethyl-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (239 mg, 98%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([N:5]([CH2:15][C:16]1([C:22]([O:24][CH3:25])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].C=O.[C:30](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:30][N:19]1[CH2:20][CH2:21][C:16]([CH2:15][N:5]([C@@H:6]2[CH2:8][C@H:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:4])[C:2]([F:1])([F:26])[F:27])([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18]1
Reactant: CC(=O)O
Reactant: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@H]2C[C@@H]2c2ccccc2)CCNCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COC(=O)C1(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-((2,2,2-trifluoro-N-((1S,2R)-2-phenylcyclopropyl)acetamido)methyl)piperidine-4-carboxylate (270 mg, 0.702 mmol) in 1,2-dichloroethane (DCE) (3 mL) and methanol (1.500 mL) were added formaldehyde (0.129 mL, 1.405 mmol) and acetic acid (0.060 mL, 1.054 mmol), and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (223 mg, 1.054 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was quenched with 10% N NaHCO3 aqueous solution and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dried under vacuum to give 265 mg of product as pale yellow oil. MS: (M+H)+=399.2.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[O:15]1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCCC1.CCCCCC.C(N(CC)CC)C.CN(C)P(N(C)C)(N(C)C)=O>[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH:20]=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[O:15]1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Li]CCCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1(C)OC(C=Cc2ccc(Cl)cc2)=CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
To a solution of dry diisopropylamine (5.0 mL, 35.7 mM) in dry tetrahydrofuran (150 mL) at -78° C., was added dropwise a 2.3N solution of n-butyllithium in hexane (15.5 mL, 35.7 mM). After the reaction solution was stirred 15 minutes, a solution of 2,2,5-trimethyl-3(2H)-furanone (3.0 g, 23.8 mM) in tetrahydrofuran (25 mL) was added dropwise. Hexamethylphosphoramide (6.4 mL, 34.7 mM) was added dropwise after 30 minutes. Finally, p-chlorobenzaldehyde 3.0 g, 2.7.8 mM) in tetrahydrofuran (25 mL) was added in one portion. The reaction solution was stirred 15 minutes when trifluoroacetic anhydride (10.5 mL, 276 mM) was added in one portion. Again the reaction mixture was stirred 15 minutes when triethylamine (5.9 mL, 48 mM) was added and the mixture was allowed to warm to room temperature. The reaction mixture was then partitioned between saturated aqueous sodium chloride (50 mL) and diethyl ether (50 mL). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (2×25 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give an orange liquid which was purified by chromatography (silica gel, pet. ether-ethyl acetate) to afford yellow crystals (3.8 g, 65% yield), m.p. 91°-92° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13](OS(C)(=O)=O)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([N:34]3[CH2:33][CH2:32][N:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:36][CH2:35]3)[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(OS(C)(=O)=O)c1nnn(-c2cccc(Cl)c2)n1
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCN(C(C)c2nnn(-c3cccc(Cl)c3)n2)CC1
Yield: 37 %

Procedure:
The title compound (12.3 mg, 37%, yellow oil) was prepared from methyl sulfonic acid 1-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]-ethyl ester (27.7 mg, 0.091 mmol) using potassium carbonate (13.8 mg, 0.100 mmol) and 1-ethoxycarbonyl piperazine (13.3 uL, 0.091 mmol) in acetonitrile (4 mL) at 80° C. overnight. The product was purified was by chromatography using a silica SPE tube (10% MeOH/CH2Cl2) followed by a second chromatography using a silica SPE tube (5% MeOH/CH2Cl2). 1H NMR (CDCl3) δ (ppm): 8.17 (s, 1H), 8.07 (dt, 1H), 7.50 (m, 2H), 4.29 (q, 1H), 4.10 (q, 2H), 3.52 (m, 4H), 2.56 (m, 4H), 1.64 (d, 3H), 1.24 (t, 3H).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[CH:25]=3)[CH:20]=[N:19][CH:18]=2)[CH2:13][CH2:12]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CO.O>[OH:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH2:29])=[O:28])[CH:25]=3)[CH:20]=[N:19][CH:18]=2)[CH2:13][CH2:12]1
Reactant: NC(=O)c1ccc2cncc(N3CCC(OCCOC4CCCCO4)CC3)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc2cncc(N3CCC(OCCO)CC3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
4-{4-[2-(Tetrahydro-2H-pyran-2-yloxy)ethoxy]piperidin-1-yl}isoquinoline-6-carboxamide (330 mg, 0.83 mmol) produced in Example 19 was dissolved in methanol-water (90:10, V/V, 15 mL), to which p-toluenesulfonic acid monohydrate (213 mg, 1.24 mmol) was then added, followed by stirring at room temperature for 24 hours. After addition of triethylamine (300 μL), the solvent was distilled off under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (ethyl acetate:methanol, 100:0-80:20, V/V) to give the desired title compound (160 mg, yield 61%).
Reaction SMILES: [CH3:1][C:2]([O:39]C(=O)C)([CH3:38])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:37])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH:34]([CH3:36])[CH3:35])[N:13]=3)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:39][C:2]([CH3:38])([CH3:1])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:37])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH:34]([CH3:35])[CH3:36])[N:13]=3)[CH2:6]1)=[O:4]
Reactant: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C(C)C)nc5ccccc54)nc3n2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A mixture of acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-isopropylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester (56 mg, 0.17 mmol) and LiOH (84 μL, 0.33 mmol, 4M solution) in THF (3 mL) and MeOH (1 mL) was allowed to stir at r.t. for 18 h. Further LiOH (495 μL, 1.98 mmol, 4M solution) and the mixture stirred at 50° C. for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-5%) then partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The resulting residue was dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 854 as a white solid (62 mg, 70%). LCMS (method I): RT 3.15 min, [M+H]+ 533.4. 1H NMR (DMSO, 400 MHz): δ 7.87-7.86 (1 H, m), 7.65-7.64 (1 H, m), 7.25-7.24 (2 H, m), 5.02 (1 H, brd s), 4.57 (1 H, t, J=8.92 Hz), 4.25 (4 H, brd s), 4.18 (1 H, dd, J=10.40, 5.66 Hz), 4.03 (1 H, t, J=9.00 Hz), 3.91-3.90 (1 H, m), 3.76 (4 H, t, J=4.59 Hz), 3.72 (3 H, s), 3.68 (1 H, dd, J=9.99, 5.41 Hz), 3.22-3.21 (3 H, m), 1.36 (3 H, s), 1.34 (3 H, s), 1.25 (6 H, d, J=2.06 Hz)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:24])=[CH:14][N:13]=3)=[CH:10][N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCNC4)C(F)=CN=3)=CN([S:58]([C:61]3C=CC(C)=CC=3)(=[O:60])=[O:59])C2=NC=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.N1CCOCC1>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:23][CH2:22][N:21]([S:58]([CH3:61])(=[O:60])=[O:59])[CH2:20]4)[C:15]([F:24])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCNC4)n3)c3cc(Cl)cnc32)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 50 °C
Yield: 37 %

Procedure:
To a stirred suspension of 2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-N-[(3S)-pyrrolidin-3-yl]pyrimidin-4-amine hydrochloride, 7c, (0.05 g, 0.10 mmol) in THF (1 mL) was added iPr2NEt (0.10 mL, 0.57 mmol) followed by methanesulfonyl chloride (0.04 mL, 0.57 mmol). The resulting homogenous light yellow mixture was heated at 50° C. for one hour at which time LCMS showed complete reaction. Morpholine (0.20 mL) was added and the solution evaporated to dryness. The resulting residue was dissolved in methanol (2 mL) then treated with 25% sodium methoxide/methanol (0.5 mL) and heated at 60° C. in sealed tube until LCMS showed reaction was complete. The resulting solution was quenched with aqueous saturated NH4Cl (0.5 mL) then evaporated to dryness. The residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to afford 15.8 mg (37% yield) of 398, as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:17])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][OH:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[O-][Si]([O-])=O.[Mg+2].[CH2:34]([O:36]CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:17])[C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([O:36][CH3:34])=[CH:13][CH:12]=1)[CH:5]=[O:6]
Reactant: CCOCC
Reactant: OCc1cc(Cl)c(Oc2ccccc2)c(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)cc(C=O)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To an ice-cold solution of 3,5-dichloro-4-phenoxybenzyl alcohol (200 mg, 0.67 mmol) in 6.7 ml of dichloromethane with 4 A sieves was added a mixture of pyridinium chlorochromate (317 mg, 1.47 mmol) and celite (317 mg). The reaction mixture was brought to room temperature and stirred for 1 h then diluted with diethyl ether and passed through a column of florisil. Removal of volatiles in vacuo afforded the title compound as a solid (175 mg, 88%). 1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.91 (s, 2H), 6.83 (d, j=6.8 Hz, 2H), 6.77 (d, j=6.8 Hz, 2H), 3.77 (s, 3H). M+1=297.
Reaction SMILES: C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41].[NH2:46][C:47]1[N:48]=[C:49]([C:56]([C:58]2[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[C:60]([O:67][CH3:68])[CH:59]=2)=[O:57])[N:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=12>C(#N)C.O.C(OCC)(=O)C>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([NH:46][C:47]1[N:48]=[C:49]([C:56](=[O:57])[C:58]2[CH:63]=[CH:62][C:61]([N+:64]([O-:66])=[O:65])=[C:60]([O:67][CH3:68])[CH:59]=2)[N:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=12)=[O:41]
Reactant: COc1cccc(C(=O)O)c1
Reactant: COc1cc(C(=O)c2nc(N)c3ccccn23)ccc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(C(=O)Nc2nc(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)n3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.78 ml (5.05 mmol) of triethylamine and then 1.17 g (2.65 mmol) of BOP are added, under a nitrogen atmosphere, to 0.8 g (2.29 mmol) of 3-methoxybenzoic acid in 20 ml of acetonitrile. After stirring at ambient temperature for 30 minutes, 0.8 g (2.29 mmol) of (1-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone obtained in example 76 is added and then the mixture is heated at 80° C. for 20 hours. The reaction medium is taken up in a mixture of water and ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel, elution being carried out with a dichloromethane/acetone (99/1) mixture. 0.618 g of an orange-colored solid is collected. Melting point: 167° C.; 1H NMR (d6-DMSO): 3.87 (3H, s), 4.02 (3H, s), 7.21 (1H, d), 7.41-7.49 (3H, m), 7.63-7.66 (2H, m), 7.95-8.10 (3H, m), 8.11 (1H, s), 9.80 (1H, d)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]1)=[O:20])=[N:5]2
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 67 %

Procedure:
Ethyl N-(6,7-difluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 67%). 1H NMR (300 MHz, CDCl3) δ 3.30 (m, 4H), 3.76 (m, 4H), 4.15 (s, 3H), 6.80-6.82 (m, 1H), 6.87-6.91 (m, 2H), 7.19-7.22 (m, 1H), 7.29 (br s, 1H), 7.49-7.51 (m, 1H), 7.60 (br s, 1H).
Reaction SMILES: [N:1]1([C:8]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:52][C:53]1[CH:58]=[CH:57][C:56]([CH:59]([C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)[N:60]2[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)=[CH:55][CH:54]=1>CN(C=O)C.C(OCC)C>[F:72][C:69]1[CH:68]=[CH:67][C:66]([CH:59]([C:56]2[CH:57]=[CH:58][C:53]([F:52])=[CH:54][CH:55]=2)[N:60]2[CH2:61][CH2:62][N:63]([C:12]([C@H:11]([NH:10][C:8]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:64][CH2:65]2)=[CH:71][CH:70]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
(R)-2-[{Azepane-1-carbonyl)-amino]}-4-methyl-pentanoic acid (0.33 g, 1.3 mmol, Example 2, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.45 mL, 2.6 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.49 g, 1.3 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 1-bis(4-fluorophenyl)methyl piperazine (0.37 g, 1.3 mmol) was then added. After additional 90 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×50 mL), brine (2×50 mL), and dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (60% EtOAc in hexane) to provide 0.58 g (86%) of the pure titled compound as a white foam: mp 71-84° C. APCI-MS m/z 527.3 (MH+).
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:18].[H][H]>O1CCOCC1.[Pd]>[ClH:18].[N:15]1[C:16]2[CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: c1ccc(CN2CCc3cccnc3C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: c1cnc2c(c1)CCNC2
Yield: 65 %

Procedure:
A methanolic solution (25 mL) of 7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridine (J. Het. Chem. 2001, 38, 535) (1.5 g, 6.69 mmol) was degassed with argon for 20 min followed by the addition of 4N HCl in dioxane (2 mL) and Pd/C (300 mg, 20 wt %) and stirred under 50 psi hydrogen pressure at room temperature for 24 h. After completion of the reaction the mixture was filtered on a short pad of celite and washed with methanol (4×25 mL). The filtrate was evaporated to dryness in vacuo and crystallized from methanol to afford the title compound as yellowish solid in 65% yield (calculated as 2HCl salt), 900 mg.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OCC)(O[CH2:15][CH3:16])(=O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[OH-].[Na+]>[CH3:1][S:2][C:3]1[N:8]=[C:7]([O:9][CH2:15][CH3:16])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: CSc1nc(O)cc(O)n1
Reactant: CCOS(=O)(=O)OCC
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(O)nc(SC)n1

Procedure:
31.6 g (0.2 mol) of 2-methylthio-4,6-dihydroxypyrimidine are added, while stirring well, to 100 cc of 2N sodium hydroxide solution 2N and the mixture is stirred at 50° for half an hour. 34.0 g (0.22 mol) of diethyl sulphate are then added dropwise and with stirring, at 50°; by the addition of 2N sodium sulphate the pH value is kept at between 8 and 8.2. Towards the end of the dropwise addition a precipitate is obtained. The mixture is subsequently stirred at 50° for 1 further hour, cooled to 0° and filtered. The precipitate is washed with cold ethanol, then with ether and dried in a high vacuum at 80°. The obtained white powder has a M.P. of 185°-187°.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[CH2:20][CH2:19]1)#[N:17]>C(OCC)(=O)C>[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][S:25]([C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:9])=[O:26])[CH2:20][CH2:19]1)#[N:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)S(=O)NC1CCN(C#N)CC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)(=O)NC1CCN(C#N)CC1
Reaction time: 16 h

Procedure:
Meta-chloroperbenzoic acid (60 mg) was added to the chloroform solution (0.5 mL) containing 1-cyano-4-(tert-butylsulfinyl-amino)piperidine at room temperature, followed by stirring at the same temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with aqueous saturated sodium hydrogencarbonate and aqueous saturated sodium chloride solutions successively, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (58 mg).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1.[ClH:43]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:43][C:10]1[CH:28]=[C:27]([F:29])[C:26]([N:30]2[C:35](=[O:36])[CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]([CH3:41])[C:31]2=[O:42])=[CH:25][C:11]=1[O:12][C:13]1[C:14]([S:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cl
Reactant: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reaction time: 1 h

Procedure:
First, 92 mg of isoamyl nitrite was added dropwise to a mixture of 0.26 g of methyl [3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridylthio]acetate, 0.10 g of copper (I) chloride, 0.21 g of copper (II) chloride, and 2.5 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.10 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridylthio]acetate (compound a-8).
Reaction SMILES: Br[CH:2]([CH2:9][CH3:10])[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:11][O:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH2:36][CH3:37])([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=3)[CH2:26][CH3:27])[CH:21]=2)[CH:16]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:2]([CH2:9][CH3:10])[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[C:30]([CH3:35])[CH:29]=3)([CH2:36][CH3:37])[CH2:26][CH3:27])[CH:21]=2)[CH:16]=1)=[O:14]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: CCC(Br)C(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 62 h
Yield: 87.6 %

Procedure:
Add 4-bromo-2,2-dimethylhexane-3-one (660 mg, 3.187 mmol) to a mixture of 6-[1-ethyl-1-(4-hydroxy-3-methylphenyl)propyl]naphthalene-2-carboxylic acid methyl ester (1.1 g, 3.035 mmol), and K2CO3 (629 mg, 4.55 mmol) in DMF (10 ml). Maintain the reaction mixture 45° C. for 14 h. Add an additional amount of 4-bromo-2,2-dimethylhexane-3-one (314 mg, 1.52 mmol) and maintain the mixture at 60° C. while stirring for 62 h. Cool the reaction mixture and dilute it with CH2Cl2, filter, and concentrate in vacuo. Chromatograph the resulting residue (CH2Cl2to 1% EtOAc/CH2Cl2) to give the title compound as a colorless viscous oil (1.299 g, 88%). 1NMR (400 MHz, CDCl3) δ ppm: 0.62 (t, J=7.2 Hz, 6H), 1.01 (t, J=7.6 Hz, 3H), 1.16 (s, 9H), 1.88 (m, 2H), 2.16 (m, 4H), 2.19 (s, 3H), 3.97 (s, 3H), 4.86 (dd, J=5.2, 1.6 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.88 (m, 2H), 7.14 (dd, J=7.2, 1.6 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 8.04 (dd, J=6.4, 2.0 Hz, 1H), 8.52 (s, 1H). High Res. ES-MS: 511.2824; calc. for C32H40O4+Na: 511.2825.
Reaction SMILES: O[C:2]1[CH:3]=C2C(=C[CH:11]=1)N=CC=C2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1CCN1CCC(N3C4C(=CC=C(C(N)=O)C=4)C=C3)CC1)[N:20](C)[CH2:19][CH2:18][CH2:17]2.C(N1C2C(=CC(OC)=C(CCN3CCC(N4C5C(=CC=C(C(N)=O)C=5)C=C4)CC3)C=2)CCC1)(=O)C>>[CH2:3]([C:15]1[C:14]([O:13][CH3:12])=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH:2]=[CH2:11]
Reactant: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C)CCC2
Reactant: Oc1ccc2ncccc2c1
Agent: COc1cc2c(cc1CCN1CCC(n3ccc4ccc(C(N)=O)cc43)CC1)N(C(C)=O)CCC2
Product: C=CCc1c(OC)ccc2ncccc12

Procedure:
The subject compound was synthesized from 6-hydroxyquinoline according to the methods described in Example 22, (1), (2), and (3).