Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+].C(O)(C)(C)C.[BH4-].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH2:29]([O:28][C@:4]1([CH2:1][CH2:2][OH:37])[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:7][C@@H:6]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:5]1[OH:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@]1(OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@@H]1O
Agent: O=[Os](=O)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2O[C@H](COCc3ccccc3)[C@@](CCO)(OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of nucleoside 2 (1.00 g, 2.09 mmol) in THF (5.4 cm3) and water (5.4 cm3) was added sodium periodate (1.34 g, 6.27 mmol) and a 2.5% solution of osmium tetraoxide in tert-butanol (w/w, 0.265 cm3, 19 μmol). The solution was stirred at room temperature for 45 min. Water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was redissolved in THF (5.4 cm3) and water (5.4 cm3). The mixture was stirred at room temperature and sodium borohydride (79 mg, 2.08 mmol) was added. After stirring for 1.5 h, water (25 cm3) was added and the solution was extracted with dichloromethane (2×50 cm3). The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate (3×30 cm3) and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (98:2, v/v) as eluent to give nucleoside 9 as a white solid material (488 mg, 48%). δH (CDCl3) 9.14 (1 H, br s, NH), 7.60 (1 H, d, J 1.1, 6-H), 7.40-7.22 (10 H, m, Bn), 6.25 (1 H, d, J 7.7, 1′-H), 4.59 (1 H, d, J 7.1 Bn), 4.49 (1 H, d, J 7.1 Bn), 4.39-3.30 (m, 8H, 4′-H, 2′-H, Bn, 5′-Ha, 5-′Hb, 2″-Ha, 2″-Hb), 2.23-2.00 (2 H, m, 1″-Ha, 1″-Hb), 1.49 (3 H, d, J 0.7 CH3). δC (CDCl3) 163.5 (C-4), 151.2 (C-2), 137.1, 136.5 (Bn), 135.7 (C-6), 128.7, 128.5, 128.2, 127.8, 127.6, 127.2 (Bn), 111.3 (C-5), 87.0, 82.7, 81.1, 78.3 (C-1′, C-2′, C-3′, C-4′), 73.7, 69.6 (Bn), 64.4 (C-5′), 57.0 (C-2″), 32.4 (C-1″), 11.8 (CH3) (Found: C, 63.9; H, 6.3; N, 5.4. C26H30N2O7,0.25H 2O requires C, 64.1; H 6.3; N, 5.75%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:35][CH2:36][O:37][CH3:38]>CN(C)C=O.O.C(Cl)Cl>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:35][CH2:36][O:37][CH3:38])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCN1CC(c2ccc3c(c2)OCCc2sc(-c4nc(C)nn4C(C)C)nc2-3)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, from Example 519, (0.300 g, 0.786 mmol) and Cesium Carbonate (0.384 g, 0.00118 mol) in N,N-Dimethylformamide (7.9 mL) was added 1-bromo-2-methoxyethane, (0.0739 mL, 0.786 mmol) dropwise. The reaction was stirred at room temperature overnight. The mixture was diluted with water and methylene chloride and extracted 3 times with methylene chloride. The crude was purified by column chromatography followed by reverse-phase HPLC to obtain 518 as a white solid (66.3 mg). MS(ESI+) 440.2. 1H NMR (400 MHz, DMSO) δ 8.28 (d, J=8.2 Hz, 1H), 7.19 (dd, J=8.2, 1.5 Hz, 1H), 7.02 (d, J=1.5 Hz, 1H), 5.76 (hept, J=6.6 Hz, 1H), 4.38-4.32 (m, 2H), 3.66-3.52 (m, 3H), 3.41 (t, J=5.0 Hz, 2H), 3.34-3.29 (m, 2H), 3.23 (s, 3H), 3.15-3.07 (m, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H)
Reaction SMILES: Br[C:2]1[C:3]([O:31][CH3:32])=[C:4]([C:9]([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2/[CH:23]=[CH:24]\[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1>[CH2:27]([N:26]([CH2:29][CH3:30])[CH2:25]/[CH:24]=[CH:23]\[C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:13]([CH2:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([O:31][CH3:32])[C:2]([C:35]2[CH:36]=[CH:37][O:33][CH:34]=2)=[CH:11][CH:10]=1)(=[O:15])=[O:14])[CH3:28]
Reactant: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(Br)c(OC)c1C(=O)OC
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Temperature: 140 °C

Procedure:
A mixture of (Z)-methyl 3-bromo-6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-2-methoxybenzoate (Intermediate 161, 0.163 g), furan-3-yl boronic acid (0.041 g), palladium (II) chloride dppf complexed with DCM (0.025 g), cesium carbonate (0.282 g) in water (0.5 ml) and dioxane (3 ml) was degassed and then heated in the microwave at 140° C. for 10 minutes. After cooling, the mixture was partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-5% to give (Z)-methyl 6-((2-(3-(diethylamino)prop-1-enyl)-4-fluorobenzenesulfonyl)methyl)-3-(furan-3-yl)-2-methoxybenzoate as an orange oil.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:40][C:41]1[CH:48]=[CH:47][CH:46]=[C:45]([Cl:49])[C:42]=1[CH:43]=O.C(O)(=O)C.N1CCCCC1>C1C=CC=CC=1>[CH3:7][O:6][C:4](=[O:5])[C:3]([C:2](=[O:1])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:43][C:42]1[C:41]([Cl:40])=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:49]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CC(=O)CCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1ccccc1COCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
A mixture of methyl 3-oxo-5-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]pentanoate (3.33 g, 6.38 mmol), 2,6-dichlorobenzaldehyde (1.12 g, 6.38 mmol), acetic acid (0.5 ml), piperidine (0.5 ml) and benzene (50 ml) was stirred for 4 hours at reflux temperature azeotropically. The reaction mixture was quenched with water (40 ml) and the whole was extracted with Et2O (20 ml×2). The combined extracts were washed with brine, dried over MgSO4, and concentrated in vacuo to afford the titled compound as a yellow oil. (quant.)
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:13]=2)[CH:8]=1)(=O)=O.[CH3:26][N:27]1[CH:31]=[CH:30][N:29]=[C:28]1[SH:32].C(N(C(C)C)CC)(C)C.O>O1CCOCC1.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(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([S:32][C:28]2[N:27]([CH3:26])[CH:31]=[CH:30][N:29]=2)[CH:16]=[CH:15]3)=[CH:22][CH:21]=1
Reactant: Cn1ccnc1S
Reactant: O=S(=O)(Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1)C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccnc1Sc1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 125 °C
Yield: 91.2 %

Procedure:
A mixture of 6-(4-fluorophenyl)-2-naphthyl trifluoromethanesulfonate (Ex 1 Step 2, 150 mg, 0.41 mmol), 1-methyl-1H-imidazole-2-thiol (47 mg, 0.41 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg) and diisopropylethylamine (0.15 mL, 0.82 mmol) in dioxane (3 mL) was heated to 125° C. under nitrogen for 15 h. The cooled reaction mixture was poured into water and extracted with ethyl acetate (x3). The combined organic layers were washed with water and brine, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to give the title compound as an oil (125 mg). 1H NMR (500 MHz, CDCl3): δ 7.90 (1H, s), 7.75 (2H, t, J=8.6 Hz), 7.66-7.59 (4H, m), 7.27 (2H, m), 7.15 (2H, m), 7.10 (1H, s), 3.65 (3H, s); m/z (ES+) 335 [MH+].
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1)=[O:35]>C1COCC1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([C:34](=[O:35])[CH2:33][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1cccc(OC)c1
Yield: 82.2 %

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (125 mg, 0.39 mmol), with triethylamine (275 uL, 1,97 mmol, 5 eq), and 2-bromo-3'-methoxyacetophenone (107 mg, 0.47 mmol, 1.2 eq) in THF (20 mL), provided 149.2 mg (81%) of L-isoleucine, N-[1-(2-(3-methoxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:13][S-:14].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([S:14][CH3:13])[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc2cc(Br)ccc2n1
Reaction time: 1 h

Procedure:
A solution of 6-Bromo-2-chloroquinoline (0.68 g, 2.8 mmol) in DMF was treated with sodium thiomethoxide (0.22 g, 3.1 mmol). After 1 h at RT, the LC-MS indicated conversion. The solution was diluted with brine and extracted with EtOAc. The organic layer was removed, dried, filtered and concentrated. The crude product was used in the next step. LC-MS (IE, m/z): 256 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=1)[CH2:9][CH3:10].[S:21]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)=[CH:22]1.NC1C=C(C=CC=1)CN>>[CH3:20][C:2]([CH3:19])([CH3:1])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][CH2:29][C:28]2[CH:31]=[CH:32][CH:33]=[C:26]([C:23]3[CH:24]=[CH:25][S:21][CH:22]=3)[CH:27]=2)[CH:13]=1)[CH2:9][CH3:10]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(N)c1
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: NCc1cccc(N)c1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(NCc2cccc(-c3ccsc3)c2)c1

Procedure:
Compounds of Examples 175 to 180 were obtained by performing the same reaction as in Example 174 except that instead of the starting compound (E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-ethyl-3-aminobenzylamine and/or 3-(3-thienyl)benzaldehyde, the corresponding 3-aminobenzylamine derivatives and/or 3-substituted benzaldehyde derivatives were used.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH:9]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[C:10]([CH3:14])([CH3:13])[C:11]#[N:12].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[CH3:13][C:10]([CH3:14])([CH:9]([C:15]1[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=1)[O:8][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[C:11]#[N:12]
Reactant: CC(C)(C#N)C(O)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(c2ccncc2)C(C)(C)C#N)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 37.3 %

Procedure:
Triethylamine (1.57 ml, 11.3 mmol) was added to a solution of 3-hydroxy-2,2-dimethyl-3-(4-pyridyl)propionitrile (1.00 g, 5.67 mmol) in dichloromethane (20 ml) at room temperature. Further, p-toluenesulfonyl chloride (1.30 g, 6.80 mmol) was added to the mixture, and the whole was warmed at 50° C. with stirring for three days. The reaction mixture was allowed to stand and then concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to give 699 mg (37.4%) of 2,2-dimethyl-3-(4-pyridyl)-3-(p-tolylsulfonyloxy)propionitrile as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[N:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:7]=[CH:6][C:5]=3[S:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: O=c1c2c(Br)csc2cnn1CCc1ccccn1
Reactant: OB(O)c1ccncc1
Product: O=c1c2c(-c3ccncc3)csc2cnn1CCc1ccccn1
Yield: 33.1 %

Procedure:
The title compound was prepared in analogy to the process described in Example 3.5 starting from 3-bromo-5-(2-pyridin-2-yl-ethyl)-5H-thieno[2,3-d]pyridazin-4-one and pyridine-4-ylboronic acid. Yield: 33.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](F)(=[O:31])=[O:30])=[CH:25][C:24]=1[NH2:33].[I-].C([NH3+])(C)(C)C>ClCCl>[NH2:33][C:24]1[CH:25]=[C:26]([S:29]([O:13][C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:31])=[O:30])[CH:27]=[CH:28][C:23]=1[O:22][CH3:21]
Reactant: COc1ccc(S(=O)(=O)F)cc1N
Reactant: COc1cc(O)cc(OC)c1OC
Agent: CC(C)(C)[NH3+]
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Oc2cc(OC)c(OC)c(OC)c2)cc1N
Reaction time: 8 h
Yield: 35 %

Procedure:
A solution of 3,4,5-trimethoxyphenol (505.7 mg, 2.75 mmol) in dichloromethane (28 mL) was treated sequentially with triethylamine (1.2 mL), 4-methoxymetanilyl fluoride (572.5 mg, 2.75 mmol), and tert-butylammonium iodide (106 mg, 0.287 mmol), stirred overnight, and washed once with 1M Na2CO3. The organic layer was separated, dried (MgSO4), filtered, and concentrated. Chromatography of the concentrate on silica gel with 40% ethyl acetate/hexanes provided 356 mg of the desired compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH2:7][O:8][N:9]=[C:10]([C:14]2[C:15](=[O:23])[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=2[OH:20])[CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[C:30]([O:23][C:15]1[CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19](=[O:20])[C:14]=1[C:10](=[N:9][O:8][CH2:7][C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH3:13])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CCCC(=NOCc1ccc(Cl)s1)C1=C(O)CC(C)(C)CC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=NOCc1ccc(Cl)s1)C1=C(OC(C)=O)CC(C)(C)CC1=O
Temperature: 0 °C

Procedure:
To a reaction mixture containing 3.6 gms (0.01 mol) of 2-{1-[(5-chlorothien-2-ylmethoxy)imino]butyl}-3-hydroxy-5,5-dimethylcyclohex-2-en-1-one and 0.87 gm (0.011 mol) of pyridine in 20 mls of methylene chloride stirred at 0° C. is added 0.89 gm (0.011 mol) of acetyl chloride. The mixture is then stirred at room temperature for 2 hours. The mixture is then worked up by washing with water, drying with anhydrous magnesium sulfate, and filtered. The filtrate is evaporated under vacuum affording 3-acetyloxy-2-{1-[(5-chlorothien-2-ylmethoxy)imino]butyl}-5,5-dimethylcyclohex-2-en-1-one.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([C:12]2[CH:17]=[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[CH:21][N:20]=3)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=2)[C:37]1=[O:51])(=O)C.[OH-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].C(Cl)Cl>[C:46]([C:41]1[CH:42]=[C:43]2[C:38](=[C:39]([F:50])[CH:40]=1)[C:37](=[O:51])[N:36]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[N:20]=[CH:21][C:22]([CH:25]5[CH2:30][CH2:29][N:28]([CH:31]([CH3:32])[CH3:33])[CH2:27][CH2:26]5)=[CH:23][CH:24]=4)[C:15](=[O:34])[N:14]([CH3:35])[N:13]=3)[C:6]=1[CH2:5][OH:4])[N:45]=[CH:44]2)([CH3:48])([CH3:49])[CH3:47]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C(C)C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)N1CCC(c2ccc(Nc3cc(-c4cccc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4CO)nn(C)c3=O)nc2)CC1
Temperature: 60 °C
Yield: 86.8 %

Procedure:
To a solution of 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-isopropylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (248 mg, 357 μmol, Eq: 1.00) in THF (5.0 ml) was added NaOH (4.29 ml, 4.29 mmol, Eq: 12.0). The reaction mixture heated at 60° C. for 18 h. The solution was cooled to room temperature, and then diluted with saturated NaHCO3 and DCM. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined, and then dried over Na2SO4. Concentrated in vacuo. The solid was triturated with Et2O and dried under vacuum to give 6-tert-butyl-8-fluoro-2-{2-hydroxymethyl-3-[5-(1′-isopropyl-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-6-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-2H-phthalazin-1-one (202 mg, 87%). LC/MS-ESI observed [M+H]+ 652. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.10 (d, J=6.42 Hz, 6H) 1.43 (s, 9H) 1.84 (br. m., 5H) 2.28 (br. m., 2H) 2.50 (br. m., 1H) 2.79 (br. s., 1H) 3.03 (d, J=10.20 Hz, 2H) 3.90 (s, 4H) 4.42 (d, J=6.80 Hz, 2H) 6.92 (s, 1H) 7.40-7.73 (m, 6H) 8.17-8.32 (m, 4H) 8.60 (s, 2H)
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](=O)[CH3:4].C(N)(=O)C1C=CC=CC=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N)(=O)C>C1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3](=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:4]
Reactant: CC(=O)N(C)C
Reactant: Nc1ccccc1
Agent: CC(N)=O
Agent: NC(=O)c1ccccc1
Solvent: c1ccccc1
Product: CC(=Nc1ccccc1)N(C)C
Yield: 53 %

Procedure:
The conventional procedure of Example 1 was repeated except that 32.7 g (0.375 mole) of N,N-dimethylacetamide was substituted for the benzamide and a solution of 11.6 g of aniline in 50 ml of benzene was utilized. Workup as in Example 1 yielded N,N-dimethyl-N-phenylacetamidine in form of a colorless oil, b.p. 73° C. at 0.12 mm of mercury in only 53% yield based on aniline or 49% yield based on POCl3 and a meager 19.5% yield based on the acetamide.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:2][CH2:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7])[CH3:24])=[CH:19][CH:18]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 96 °C
Yield: 60.1 %

Procedure:
1-chloro-5-methyl-3-phenylhex-5-en-3-ol (1.28 g, 5.7 mmol), (S)-1-(4-bromophenyl)ethanamine (1.37 g, 1.2 equiv), KI (995 mg, 1.05 equiv), K2CO3 (1.57 g, 2 equiv) were mixed with acetonitrile (15 mL) and heated to reflux (oil bath 96° C.) for overnight. After being cooled to rt, the mixture was filtered, concentrated, and purified by chromatography on a 40-g silica gel column, eluted with 0˜8% MeOH in CH2Cl2, to afford 1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhex-5-en-3-ol (1.33 g, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1Cl)[CH3:2].Cl.[CH2:14]([O:21][NH2:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH2:14]([O:21][NH:22][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1NOCc1ccccc1
Yield: 52.3 %

Procedure:
2-Chloro-nicotinic acid ethyl ester (4.55 g, 24.6 mmol), O-benzylhydroxyamine hydrochloride (7.85 g, 49.2 mmol) and N,N-diisopropylethylamine (6.36 g, 49.2 mmol) in 10 mL 1,4-dioxane were reacted in a sealed tube at 120° C. for 48 hours. The reaction mixture was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The aqueous layer was re-extracted with ethyl acetate (2×50 mL). The organic layers were combined and dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (9:1) to provide the title compound (3.5 g, 53%). MS (DCI) m/z 273 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8](OC)=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:29].[CH3:30]O>O>[CH3:1][O:2][C:3]1[CH:12]=[C:7]2[C:6](=[CH:5][C:4]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][Cl:19])[N:13]=[CH:30][NH:29][C:8]2=[O:9]
Reactant: CO
Reactant: [NH4+]
Reactant: COC(=O)c1cc(OC)c(OCCCCCl)cc1N
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
In a 10 mL volume stainless pressure-resistant vessel equipped with a stirrer and a thermometer were placed 1.1 g (3.5 mmol) of methyl 5-methoxy-4-(4-chlorobutoxy)-anthranilate, 0.92 g (8.8 mmol) of methyl orthoformate, 0.67 g (8.8 mmol) of ammonium acetate, and 5 mL of methanol. The vessel was closed, and the reaction was carried out at 90-95° C. for 8 hours. After the reaction was complete, 50 mL of water was added to the reaction mixture. The aqueous reaction mixture was stirred at 25° C. for one hour, to precipitate a crystalline product. The crystalline product was collected by filtration and dried at 60° C. under reduced pressure, to give 0.94 g (isolated yield: 96%) of 6-methoxy-7-(4-chlorobutoxy)quinazolin-4-one as a gray crystalline product.