Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:12](S(C(F)(F)F)(=O)=O)[S:13]([C:16]([F:19])([F:18])[F:17])(=O)=[O:14]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:14])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 70.3 %

Procedure:
Quinolin-6-ol (2.9 g, 20 mmol) was dissolved in pyridine (30 mL). The mixture was cooled to 0° C. in an ice bath under nitrogen and Tf2O (4 mL, 24 mmol) was added to the reaction mixture slowly. The reaction mixture was stirred at room temperature for 5 hours, before partitioning between dichloromethane (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was separated and washed with brine (5×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give 3.9 g of trifluoromethanesulfonic acid quinolin-6-yl ester as a brown oil (70% yield).
Reaction SMILES: [CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@@H:8]([CH2:18][C:19]#[N:20])[CH2:7][N:6]1[CH2:21][CH2:22][CH3:23].N.C(OCC)(=[O:27])C>Br.C(O)(=O)C>[CH3:1][C:2]1[NH:16][C:15]2[C:17]3[C:3]=1[CH2:4][C@@H:5]1[C@@H:10]([C:11]=3[CH:12]=[CH:13][CH:14]=2)[CH2:9][C@@H:8]([CH2:18][C:19]([NH2:20])=[O:27])[CH2:7][N:6]1[CH2:21][CH2:22][CH3:23]
Reactant: CCOC(C)=O
Reactant: CCCN1C[C@H](CC#N)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Agent: Br
Agent: N
Solvent: CC(=O)O
Product: CCCN1C[C@H](CC(N)=O)C[C@@H]2c3cccc4[nH]c(C)c(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
922 mg of (2-methyl-6-n-propyl-8beta-ergolinyl)-acetonitrile (3 mmol) is dissolved in 15 ml of a 30% solution of HBr in glacial acetic acid and stirred for 3 hours at room temperature. The mixture is mixed with ice, made alkaline with ammonia and shaken with ethyl acetate. The organic phases are dried and concentrated by evaporation. The residue is chromatographed on silica gel with acetone/methanol and crystallized from ethyl acetate, yield 421 mg (43% of theory), [α]D =-67° (0.5% in pyridine).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][C:21]2=[O:30])=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[OH-].[K+].Cl>C(O)C.O>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[NH:7][C:8]=1[CH:19]=[C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=2)[NH:22][C:21]1=[O:30])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c(C(=O)OCC)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Cl)cc32)c1CCC(=O)O
Temperature: 95 °C
Yield: 99.4 %

Procedure:
A mixture of 4-(2-ethoxycarbonylethyl)-3-methyl-5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester (346 mg) and potassium hydroxide (560 mg) in ethanol (5 mL) was heated to 95° C. and then cooled, upon which red crystals formed. The crystals were dissolved in water and acidified with 2 N hydrochloric acid to pH 2. The precipitate was filtered, washed with water, and dried in a vacuum oven overnight to give 299 mg (100%) of 4-(2-carboxyethyl)-3-methyl-5-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid as a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:12]2[CH2:13][CH2:14][CH2:15][N:10]([CH2:9][C:8]3[CH:27]=[CH:28][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=3)[C:11]2=[O:26])=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc([N+](=O)[O-])cc3)C2=O)cc1
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)c1ccc(CN2CCCN(Cc3ccc(N)cc3)C2=O)cc1

Procedure:
To a solution of 1-(4-tert-butylbenzyl)-3-(4-nitrobenzyl)tetrahydropyrimidin-2-one (K) (500 mg, 1.31 mmol) in abs. MeOH (50 mL) palladium on charcoal (5%, 600 mg) was added. The reaction mixture was subjected to a hydrogen pressure of 2 bar for 20 min at RT. The catalyst was separated by filtration through Celite and the filtrate was concentrated in vacuo. The desired product 1-(4-aminobenzyl)-3-(4-tert-butylbenzyl)-tetrahydropyrimidin-2-one (L) was obtained as a colorless oil (364 mg, 79% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:14])=[O:13].[N:35]([Si](C)(C)C)=[N+:36]=[N-:37].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[S:24][C:25]3[CH:31]=[CH:30][C:29]([C:32]4[NH:37][N:36]=[N:35][N:33]=4)=[CH:28][C:26]=3[N:27]=2)[CH:19]=[C:18]([Cl:34])[CH:17]=1)(=[O:13])=[O:14]
Reactant: N#Cc1ccc2sc(Oc3cc(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)c3)nc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)cc(Oc2nc3cc(-c4nnn[nH]4)ccc3s2)c1)c1ccc(C(F)(F)F)cc1Cl
Temperature: 90 °C
Yield: 85.1 %

Procedure:
To a solution of 2-Chloro-N-[3-chloro-5-(5-cyano-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide (Example 286, 55 mg, 0.1 mmol) in 5 mL of toluene was added azidotrimethylsilane (Aldrich, 26 uL, 0.2 mmol) and dibutyltin oxide (Aldrich, 3 mg, 0.01 mmol). The mixture was heated at 90° C. overnight till there was no starting material remained by TLC. Cooled to room temperature, 1N HCl and EtOAc was added. The mixture was extracted 3× with EtOAc (30 mL). The organic layers were washed twice with a brine solution (300 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography, eluted with 10% EtOAc/CH2Cl2 then 10% MeOH/CH2Cl2 to give 50 mg (85%) of product. 1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J=8.2 Hz, 1H), 8.30 (d, J=1.6 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.19 (s, 1H), 8.03 (dd, J=8.4, 1.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.18 (t, J=2.0 Hz, 1H), 7.12 (t, J=1.9 Hz, 1H). MS (EI): m/z 585 (M−H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][C:20]=1[CH2:27][OH:28])[CH:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][C:31](OC(C)=O)=[O:32].CCN(CC)CC.N#N>C(Cl)Cl>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:31](=[O:32])[CH3:30])=[CH:21][C:20]=1[CH2:27][OH:28])[CH:8]1[C:17]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CN)cc1CO)C1CCCc2cccnc21
Reactant: CC(=O)OC(C)=O
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc(CN(C(=O)OC(C)(C)C)C2CCCc3cccnc32)c(CO)c1
Yield: 99.6 %

Procedure:
To a solution of (4-aminomethyl-2-hydroxymethyl-benzyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester (0.86 g, 2.17 mmol) dissolved in CH2Cl2 (15 mL) was added Ac2O (0.21 mL, 2.17 mmol) and Et3N (0.31 mL, 2.17 mmol). The solution was stirred for 30 minutes under a positive pressure of N2. The reaction mixture was quenched with saturated aqueous NaHCO3 (25 mL) and extracted with CH2Cl2 (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford [4-(acetylamino-methyl)-2-hydroxymethyl-benzyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-carbamic acid tert-butyl ester as a white solid (0.95 g, 99%). 1H NMR (CDCl3) δ 1.06 (s, 9H), 1.65 (m, 1H), 2.01 (m, 3H), 2.08 (m, 1H), 2.70 (m, 2H), 3.87 (d, 1H, J=15.0 Hz), 4.09 (m, 1H), 4.41 (d, 3H, J=6.0 Hz), 5.07 (d, 1H, J=12.0 Hz), 5.56 (d, 1H, J=12.0 Hz), 5.96 (m, 1H), 6.98 (m, 1H), 7.15 (s, 2H), 7.32 (d, 1H, J=6.0 Hz), 7.41 (s, 1H), 8.15 (d, 1H, J=3.0 Hz). Deprotection with TFA following General Procedure F gave N-{3-hydroxymethyl-4-{(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl}-benzyl}-acetamide as an off-white solid. 1H NMR (CDCl3) δ 1.79 (m, 2H), 1.94 (m, 1H), 2.00 (s, 3H), 2.26 (m, 1H), 2.77 (m, 2H), 3.89 (m, 2H), 4.13 (d, 1H, J=12.0 Hz), 4.41 (m, 3H), 4.79 (d, 1H, J=12.0 Hz), 7.05 (m, 1H), 7.20 (m, 1H), 7.31 (m, 1H), 7.40 (m, 2H), 8.33 (d, 1H, J=3.0 Hz).
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.C(Cl)Cl.[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C@H:34]1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][OH:75])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.S(=O)(=O)(O)O>C(O)C>[CH2:25]([O:32][C@@H:33]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][C@H:34]1[O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH:74]=[O:75])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: OCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCO
Product: O=CCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
(b)(i) PDC oxidation of 10-(2,3,4,6-tetra-O-benzyl-β-D-cralactopyranosyloxy)-n-decanol. Under an atmosphere of nitrogen, pyridinium dichromate (460 mg, 1.222 mmol) was added to a dry methylene chloride solution (10 mL) of 10-(2,3,4,6-tetra-O-benzyl-β-D-galactopyrano-syloxy)-n-decanol (570 mg, 0.818 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 20 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 20% ethyl acetate in hexanes) afforded 374 mg (0.539 mmol, 66%) of 10-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-decanal as a clear oil. Rf =0.61 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3 300 MHz) δ: 9.77 (t, J=1.5 Hz, 1H), 7.30 (m, 20 H), 4.97 (dd, J=12.0, 2.7 Hz, 2H), 4.78 (d, J=11.1 Hz, 1H), 4.77 (d, J=4.5 Hz, 1H), 4.65 (d, J=12 Hz, 1H), 4.46 (d, J=4.2 Hz, 2H), 4.38 (d, J=7.8 Hz, 1H), 3.95 (m, 1H), 3.84 (dt, J=10.2, 1.8 Hz, 1H), 3.50 (m, 6H), 2.40 (dt, J=7.5, 1.8 Hz, 2H), 1.65 (m, 6H), 1.30 (m, 10 H); MS (FAB+): 701.0 ((M+Li)+, 100), 455.1 (4), 181.1 (19), 160.0 (8).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[N:6][CH:7]=1.[OH-].[NH4+:11]>CO.[Cu]Br>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([NH2:11])[CH:7]=[N:6][CH:5]=1
Reactant: [NH4+]
Reactant: COc1cncc(Br)c1
Agent: [Cu]Br
Agent: [OH-]
Solvent: CO
Product: COc1cncc(N)c1
Temperature: 171 °C

Procedure:
Crude 5-bromo-3-methoxypyridine (3.50 g, 18.62 mmol) was dissolved in methanol (50 mL) and added to concentrated ammonium hydroxide (29.7%, 14.8 M, 50 mL) and copper(I) bromide (2.67 g, 18.62 mmol) in a heavy-walled glass pressure-tube apparatus. The tube was flushed with nitrogen and sealed. The mixture was stirred and heated at 170-172° C. (oil bath temperature) for 24 h. After cooling, the solution was concentrated by rotary evaporation to a gummy residue. The residue was diluted with sodium carbonate solution (17.6%, 200 mL) and extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation to give 1.26 g of a cream-brown solid. The aqueous phase was re-extracted with CH2Cl2 (4×50 mL). The combined CH2Cl2 extracts were similarly dried and concentrated to give an additional 0.34 g of a cream-brown solid, bringing the total yield to 1.60 g (69.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1
Reactant: Cc1n[nH]c(=O)c(-c2ccsc2)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2ccsc2)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
1.38 g of 5-(4-chloro-phenyl)-6-methyl-4-(3-thienyl)-2H-pyridazin-3-on e and 6 ml of phosphorus oxychloride were mixed. The mixture was stirred for 1 hour on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue was added ethyl acetate and ice water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-partitioned. The organic layer was washed with brine three times, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 1.34 g of 3-chloro-5-(4-chlorophenyl)-6-methyl-4-(3-thienyl)pyridazine (hereinafter, described as compound (9) of the present invention.).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.[OH-].[K+].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>O>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[CH:16][CH:15]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CC(=O)C(Cc2ccc(Cl)cc2)C(=O)C1
Temperature: 59 °C
Yield: 42 %

Procedure:
449 g (3.21 mols) dimedone (5,5-dimethylcyclohexane-1,3-dione) were added to a solution of aqueous potassium hydroxide comprising 166 g of 85% potassium hydroxide (2.52 moles) in 700 ml of water. The mixture was then warmed and a clear orange solution was obtained at 47° C. The solution was then heated to 59° C. and 544 g (3.21 mols) molten 4-chlorobenzyl chloride were added over a period of 1 hour with further heating to 85° C. Heating was continued for a further 21/2 to 3 hours up to a temperature of 100° C. The mixture was then cooled, the solid product filtered off, washed with water and dried in a vacuum oven at 50° C. The crude solid (815 g) was then dissolved in 2400 ml methanol at reflux and 200 ml water added to produce a permanent cloudiness. The mixture was then allowed to cool to room temperature overnight with stirring The solid so obtained was filtered, washed with about 400 ml cold methanol and dried in a vacuum oven to produce 340 g 2-(4-chlorobenzyl)-5,5-dimethylcyclohexane-1,3-dione as a white solid, m.pt. 188°-190° C. Yield: 42%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[C:6]([O:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)[C:7]=1[C:8]#[N:9].[C:17]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])[CH2:22][CH2:21]1)(=O)[CH3:18].ClCCl.N>CO>[CH:11]1([O:10][C:6]2[CH:5]=[C:4]([O:15][CH3:16])[CH:3]=[C:2]([N:1]=[C:17]([N:20]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:28])[CH2:22][CH2:21]3)[CH3:18])[C:7]=2[C:8]#[N:9])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cc(N)c(C#N)c(OC2CCC2)c1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OC2CCC2)c1

Procedure:
The subtitle compound was prepared from 3-amino-4-cyano-5-cyclobutyloxyanisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following the procedure described in Example 14(d) (93%). Rf 0.52 (dichloromethane:methanol:0.880 aqueous ammonia, 92:7:1, v/v). MS m/z 456 (MH)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([N:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=[C:17]3[N:16]([CH3:26])[C:15]2=[O:27])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][N:23]([CH3:25])[C:20]1[N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:27])[N:16]([CH3:26])[C:17]2=[CH:22][CH:21]=1
Reactant: CN(C)c1ccc2c(n1)n(C1CCN(C(=O)OC(C)(C)C)CC1)c(=O)n2C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc2c(n1)n(C1CCNCC1)c(=O)n2C
Reaction time: 0.58 h
Yield: 96 %

Procedure:
To a stirring solution of 1.07 g (0.0028 mol) of 4-(5-dimethylamino-1-methyl-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (7 mL) was added 7 mL of TFA. After 35 min, the solvent was removed. The residue was partitioned between EtOAc (200 mL) and 1 N NaOH (150 mL). The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na2SO4 and concentrated to afford 0.74 g (96%) of 5-dimethylamino-1-methyl-3-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one as a white/pink solid. 1H NMR (400MHz, CDCl3): 6.95 (d, J=8.3 Hz, 1H), 6.08 (d, J=8.3 Hz, 1H), 4.35 (ft, J=12.1 Hz, 4.0 Hz, 1H), 3.25 (s, 3H), 3.14 (d, J=12.4 Hz, 2H) 2.97 (s, 6H), 2.66 (td, J=12.9 Hz, 1.3 Hz, 2H), 2.53 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.69 (d, J=11.9 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.Cl.[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35]([N:37]1[CH2:38][CH2:39][N:40]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH2:41][CH2:42]1)=[O:36]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CC3)cc1
Reactant: O=C(c1ccco1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCN(C(=O)c5ccco5)CC4)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.5 %

Procedure:
In DMF (3 ml) was dissolved N-[4-(chloromethyl)-phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the solution were added 1-(2-furoyl)piperazine hydrochloride (109 mg) and potassium carbonate (268 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water (50 ml). The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with ethyl acetate-diisopropylether to give N-[4-[1-(2-furoyl)-4-piperazinylmethyl]phenyl]-7-(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (Compound 44) (112 mg) as colorless amorphous.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][C:49]([F:52])([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][O:54][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][C:49]([F:51])([F:52])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:53][OH:54])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CC(=O)Cl
Solvent: CO
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethyl-silane 7g (4.19 g, 4.78 mmol) was dissolved in 30 mL methanol, followed by addition of acetyl chloride (51 μL, 0.72 mmol). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system D to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2,2-trifluoroethoxy)phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methanol 7h (1.1 g, white grease), yield: 30.1%. 1H NMR (400 MHz, DMSO-d6): δ 7.55-7.43 (m, 2H), 7.39-7.28 (m, 6H), 7.28-7.16 (m, 9H), 7.11-7.03 (m, 1H), 7.01 (dd, 2H), 6.90 (d, 2H), 4.91-4.73 (m, 4H), 4.73-4.58 (m, 3H), 4.42 (d, 1H), 4.17-3.87 (m, 4H), 3.83-3.62 (m, 4H), 3.53 (dd, 1H), 3.24 (d, 1H), 3.08-2.86 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([C:10]2[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][CH:15]=2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:3]=1.C(N(CC)CC)C.Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:4]2[CH:5]=[C:6]([C:10]3[CH2:11][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:14][CH:15]=3)[C:7]3[CH2:8][O:9][C:47](=[O:49])[NH:1][C:2]=3[N:3]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c(CO)c(N)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2-c2cc(C3=CCCN(C(=O)OC(C)(C)C)C3)c3c(n2)NC(=O)OC3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 2′-amino-3′-(hydroxymethyl)-6′-{2-[(4-methoxybenzyl)oxy]phenyl}-5,6-dihydro-3,4′-bipyridine-1(2H)-carboxylate (25.0 mg, 0.05 mmol), which was obtained in the step (2) of Example 11-4, and triethylamine (0.02 mL, 0.14 mmol) in THF (3.0 mL) was added a solution of triphosgene (5.7 mg, 0.02 mmol) in THF (3.0 mL), and the stirring was continued for 30 min. The reaction mixture was allowed to warm to room temperature. The reaction was cooled to 0° C. and then quenched by an addition of saturated aqueous NaHCO3 solution, extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by preparative silica gel TLC (10% acetone in chloroform) to give tert-butyl 5-(7-{2-[(4-methoxybenzyl)oxy]phenyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate as a white solid. (21.7 mg, yield 83%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:15])=[CH:10][C:11](=O)[NH:12][N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([Cl:18])=[CH:10][C:9]=2[CH3:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(=O)[nH]nc1-c1ccc(Br)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)nnc1-c1ccc(Br)cc1

Procedure:
A 2.0 g. portion of 6-(p-bromophenyl)-5-methyl-3(2H)-pyridazinone and 20 ml. of phosphorus oxychloride are heated on a steam bath for 3 hours. The reaction mixture is poured slowly into crushed ice. The excess phosphorus oxychloride is decomposed. The solid which forms is recovered by filtration, washed with water, dried and recrystallized twice from chloroform, yielding 6-(p-bromophenyl)-5-methyl-3-chloropyridazine, m.p. 197°-200° C.