Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2[CH:12]=[CH:13][CH:14]=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CCCC1.[Br:39][C:40]1[CH:41]=[N:42][C:43]([N:46]2[C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:55]([OH:57])=O)[CH:53]=3)[C:48]([S:58][CH3:59])=[CH:47]2)=[N:44][CH:45]=1>CN(C=O)C>[Br:39][C:40]1[CH:45]=[N:44][C:43]([N:46]2[C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:55]([N:15]4[CH2:14][CH2:13][CH2:12][CH2:10]4)=[O:57])[CH:53]=3)[C:48]([S:58][CH3:59])=[CH:47]2)=[N:42][CH:41]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)O)ccc12
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cn(-c2ncc(Br)cn2)c2cc(C(=O)N3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
HATU (3.1 g, 8.24 mmol), diisopropylethylamine (3.6 ml, 20.6 mmol) and pyrrolidine (0.6 g, 8.24 mmol) were added to an ice cooled suspension of 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylic acid (2.5 g, 6.86 mmol) in DMF (20 mL). The resulting mixture was stirred at room temperature for 16 h and then quenched with crushed ice. The precipitating solid was filtered off, washed with water and dissolved in dichloromethane. The organic phase was dried over sodium sulfate and evaporated. White solid. Yield: 2.1 g (73% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[C:30]4[CH2:37][CH2:36][CH:35]([OH:38])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:9][N:10]([CH:18]([CH3:20])[CH3:19])C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:9][NH:10][CH:18]([CH3:20])[CH3:19])[C:21]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[C:30]4[CH2:37][CH2:36][CH:35]([OH:38])[C:31]=4[N:32]=[CH:33][N:34]=3)[CH2:27][CH2:28]2)=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)NCC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 2-(4-chlorophenyl)-3-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (49 mg, 0.09 mmol) in DCM (10 mL) was added HCl in dioxane (4M, 2 mL). The mixture was stirred at room temperature overnight. The solvent was removed to afford the 2-(4-chlorophenyl)-1-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (46 mg, 99%). 1H NMR (D2O, 400 MHz) δ 8.38-8.36 (m, 1H), 7.37-7.34 (m, 2H), 7.22-7.19 (m, 2H), 5.18-5.10 (m, 1H), 4.34-4.28 (m, 1H), 4.10-3.00 (m, 12H), 2.50-2.40 (m, 1H), 1.85-1.75 (m, 1H), 1.28-1.26 (m, 6H), 1.20-1.13 (m, 3H). MS (APCI+) [M+H]+444.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CCN(C(C)C)C(C)C.CN(C(ON1[N:37]=[N:36][C:31]2[CH:32]=[CH:33][CH:34]=[N:35][C:30]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[N:46]1[CH:51]=[CH:50][C:49]([C:52]2C3CNCCC=3NN=2)=[CH:48][CH:47]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:34]1[CH2:33][CH2:32][C:31]2[NH:36][N:37]=[C:52]([C:49]3[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=3)[C:30]=2[NH:35]1)=[O:11]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: c1cc(-c2n[nH]c3c2CNCC3)ccn1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccccc1Cl)C1CCc2[nH]nc(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(2-chlorophenyl)acetic acid (34 mg, 0.2 mmol) and DIEA (89 μA, 0.6 mmol) in DMF (1 ml) at 0° C., was added HATU (91 mg, 0.24 mmol). After stirring for 30 min, (3-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine hydrochloride was added. The reaction mixture was warmed to room temperature and continued stirring for 2 hour. Water was added and the reaction mixture was extracted with ethyl acetate (10 ml). The organic component was washed with water (5 ml) and brine (5 ml). After dry over sodium sulfate, solvent was removed under vacuum and the residue was purified using prep-HPLC to give the desired compound as white solid (20 mg). LC-MS found 353.22 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH3:19])=[C:9]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(C(C)(C)C)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)C)cc1C#C[Si](C)(C)C
Yield: 69.6 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 5-tert-butyl-2-methyl-phenyl ester (Intermediate 108, 0.28 g, 0.94 mmol), triethyl amine (3 mL), trimethylsilyl acetylene (1 mL, 7 mmol), N,N-dimethylformamide (6 mL) and dichlorobis(triphenylphosphine)palladium(II) (0.053 g, 0.076 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using hexane as the eluent, the title compound (0.16 g, 69%) was obtained. 1H NMR (300 MHz, CDCl3): δ 7.44(d, J=1.7 Hz, 1H), 7.22(dd, J=8.2, 1.7 Hz, 1H), 7.10(d, J=8.2 Hz, 1H), 2.39(s, 3H), 1.28(s, 9H), 0.26(s, 9H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[C:13](C(N[O-])=O)=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+].C(=O)=O.C(#[N:32])C>>[CH2:1]([O:11][C:12]1[C:13]([NH2:32])=[CH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC#N
Reactant: CCCCCCCCCCOc1cc2ccccc2cc1C(=O)N[O-]
Agent: O=C=O
Agent: [Na+]
Product: CCCCCCCCCCOc1cc2ccccc2cc1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Two liter of acetonitrile was added to 510 g of sodium 3-decyloxy-2-naphthalenehydroxamate obtained above, and stirred for about 30 minutes at 60° C. Thereupon, evolution of carbon dioxide gas was confirmed. The reaction mixture was further stirred with heating for 1 hour. Then, the insoluble matter (3,3'-didecyloxy-2-2'-dinaphthylurea) was filtered out, and the filtrate was concentrated. The residue was dissolved in 1 liter of ethyl acetate, and washed 3 times with 500 ml of water. The organic layer was separated from the aqueous layer, dried with Glauber's salt, and then concentrated. Thus, 323 g of whitish orange 3-decyloxy-2-naphthylamine (Compound 1) was obtained in a 84% yield. The melting point of the product was 64°-65.5° C.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][CH:18]=1)[C:9]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[O:10])([O-:5])=[O:4].[CH2:19](I)[CH3:20].C(OCC)(=O)C>CN(C)C=O>[CH2:19]([N:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9](=[O:10])[C:8]1[CH:16]=[CH:17][CH:18]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=1)[CH3:20]
Reactant: O=C(c1cccc([N+](=O)[O-])c1)c1ccc[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1cccc1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 78.5 %

Procedure:
3.2 g (130 mmol) of 50% sodium hydride were suspended, under nitrogen atmosphere, in 100 ml of anhydrous dimethylformamide. A solution of 12 g (55 mmol) of 2-(3'-nitrobenzoyl)pyrrole, prepared, for example, as described in Preparation 3A, in 50 ml of dimethylformamide was added thereto, at room temperature and under stirring. The resulting mixture was stirred for an additional hour and then treated dropwise with a solution of 11.2 ml (70 mmol) of ethyl iodide in 30 ml of dry dimethylformamide. The reaction mixture was stirred for an additional hour and then poured into 500 ml of ethyl acetate. The organic extract was washed with water (5×250 ml), dried and evaporated in vacuo. Crystallization of the residue from acetone-hexane afforded 10.55 g (78%) of 1-ethyl-2-(3'-nitrobenzoyl)pyrrole, the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([CH2:24]Cl)=[CH:18][C:19](=[O:23])[O:20]2)=[CH:15][CH:14]=1.BrC1C(C)=CC([O:31]CCC(C)(O)C)=CC=1C.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[CH2:4][CH2:5][C@H:6]2[O:12][C:13]1[CH:14]=[CH:15][C:16]2[C:17]([CH2:18][C:19]([OH:31])=[O:23])=[CH:24][O:20][C:21]=2[CH:22]=1
Reactant: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Reactant: O=c1cc(CCl)c2ccc(O[C@@H]3CCc4c(Br)ccc(F)c43)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1coc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc12
Temperature: 25 °C

Procedure:
To 15.0 g (35.4 mmol) 7-((R)-4-bromo-7-fluoroindan-1-yloxy)-4-chloromethyl-chromen-2-one (product from step 2) in 45 ml EtOH, 9.29 ml (177 mmol) aq. NaOH (50%) is added. The funnel is rinsed with 50 ml water and the mixture is heated to reflux for approx. 0.5 h. Then, over a time period of 30 min a mixture of 30 ml water and 14.7 ml (177 mmol) conc. HCl (37%) is added. The suspension is cooled to r.t., the product is filtered off, washed with EtOH/water (1:1, 2×30 ml) and dried. Yield: 14.0 g; Rf=0.38 (silica gel, PE/EtOAc/AcOH=6/4/0.1); Mass spectrum (ESI): m/z=405 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:16][CH2:15][N:14]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CCN(CC)CC>C(Cl)Cl>[CH:12]([CH:13]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH2:16][CH2:15][N:14]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:11]
Reactant: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C1CCN(C(=O)OC(C)(C)C)C(C=O)C1
Reaction time: 0.5 h

Procedure:
At −78° C., to a solution of Oxalyl Chloride (0.24 mL, 2.75 mmol) in DCM (4 mL), DMSO (0.43 mL, 6.04 mmol) was added. The reaction solution was stirred at the same temperature for 30 min and then a solution of tert-butyl 2-(hydroxymethyl)-4-(2-methoxyphenyl)piperidine-1-carboxylate 125 (580 mg, 1.8 mmol) in DCM (2 mL) was added. The reaction mixture was stirred at −78° C. for 30 min, followed by the addition of Et3N (1.1 mL, 7.32 mmol). The reaction mixture was warmed up to r.t overnight. The reaction was quenched with water and the mixture was extracted with ethyl acetate. After removal of solvent, the crude product of tert-butyl 2-formyl-4-(2-methoxyphenyl)piperidine-1-carboxylate 126 was obtained without further purification. LC/MS RT (5 min method)=2.406 min. Mass observed: 264.1 (M-Buthyl+H).
Reaction SMILES: [CH2:1]1[C@@H:5]([C:6]([OH:8])=[O:7])[NH:4][CH2:3][C@@H:2]1[OH:9].C([O-])([O-])=O.[K+].[K+].[Cl:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1.Cl>O.C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([N:4]2[CH2:3][C@H:2]([OH:9])[CH2:1][C@H:5]2[C:6]([OH:8])=[O:7])=[O:26])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a clear solution of L-trans-4-hydroxy-proline (10 g) (0.076 mol) and K2CO3 (15.7 g) (1.1 eq.) in 100 mL of water and 10 mL of THF, was added by portions 3,5-dichlorophenyl isocyanate (15.7 g) (1.1 eq.). The white suspension was stirred at RT overnight. The aqueous mixture was acidified with conc. HCl, ,then extracted with EtOAc. The organic extracts were combined, washed with water, dried over MgSO4, filtered, and the solvent removed in vacuo to afford the titled compound (19 g) (yield 78.5%). 1H NMR (DMSOd6): 8.7 (1H,COOH), 7.65 (2H,d), 7.1 (1H,m), 5.2 (1H,NH), 4.4 (2H,m), 3.6 (1H,dd), 3.45 (1H,d), 2.1–2.25 (1H, m), 1.85–2.05 (1H,m).
Reaction SMILES: [C:1]1([P:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([CH3:18])[CH:14]=[CH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OO.[O-:27]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:19]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([CH3:18])[CH:14]=[CH:13]3)=[O:27])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC1C=Cc2cccc(P(c3ccccc3)c3ccccc3)c2N1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Product: CC1C=Cc2cccc(P(=O)(c3ccccc3)c3ccccc3)c2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-diphenylphosphino-2-methyl-1,2-dihydroquinoline (2) (10.5 g, 32 mmol) in CH2Cl2 (100 mL) was added H2O2 (6.6 mL, 30% w/w in H2O, 63.9 mmol) at 0° C. and the solution was stirred at room temperature for 1 hour. The solution was then cooled to 0° C., saturated aqueous Na2SO3 solution (10 mL) was added and the mixture was warmed to room temperature. Products were extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give 5 as a yellow oil (11 g, quantitative). 1H NMR (400.13 MHz, CDCl3) δ 7.7-7.6 (m, 4H, Ph-H), 7.6-7.5 (m, 2H, Ph-H), 7.5-7.4 (m, 4H, Ph-H), 6.97 (bs, 1H, N1—H), 6.87 (d, 1H, J=7.2 Hz, C5—H), 6.55 (ddd, 1H, J=14.0, 8.0, 1.6 Hz, C7—H), 6.36 (ddd, 1H, J=10.0, 7.6, 2.8 Hz, C6—H), 6.22 (d, 1H, J=10.0 Hz, C4—H), 5.51 (ddd, 1H, J=10.0, 4.0, 2.0 Hz, C3—H), 4.43 (m, 1H, C2—H), 1.17 (d, 3H, J=6.8 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 148.2 (d, J=5.1 Hz), 146.0 (d, J=6.1 Hz), 135.7 (d, J=8.1 Hz), 134.8, 132.4, 131.3 (d, J=5.1 Hz), 131.0 (d, J=11.1 Hz), 130.8 (d, J=10.1 Hz), 130.7 (d, J=10.1 Hz), 130.1, 129.2, 127.2 (d, J=12.1 Hz), 126.6 (d, J=13.1 Hz), 126.3, 125.0 (d, J=8.1 Hz), 124.1 (d, J=13.1 Hz), 122.8, 121.1, 119.7 (d, J=8.1 Hz), 113.6 (d, J=14.1 Hz), 107.3, 106.2, 46.9, 23.5 ppm; 31P NMR (161.97 MHz, CDCl3) δ 36.0 ppm.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:6]=2[C:5](=[O:16])[NH:4][C:3]1=[O:17].CN(C)C(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]1[N:41]=[C:40]([CH3:42])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1>O>[CH3:42][C:40]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[C:32]([CH2:31][N:4]2[C:5](=[O:16])[C:6]3[N:7]([CH2:12][C:13]#[C:14][CH3:15])[C:8]([Br:11])=[N:9][C:10]=3[N:2]([CH3:1])[C:3]2=[O:17])[N:41]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Reactant: Cc1nc(CCl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
3-Methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (10 gm) and N,N-dimethylacetamide (150 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (9.3 gm) and 2-(chloromethyl)-4-methylquinazoline (6.8 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 90° C. and maintained the temperature for 8 hours. The reaction mixture was cooled to 30° C. and water (450 mL) was added and the mixture was stirred for 1 hour at 30° C. The solid formed was collected by filtration and washed with water (150 mL). The wet cake was charged into 500 mL round bottomed flask and toluene (220 mL) was added and the mixture was heated to reflux temperature and maintained for 1 hour. The mixture was cooled to 10° C. and maintained for 2 hours. The solid was collected by filtration and washed with toluene (50 mL). The solid was dried in oven under vacuum at 80° C. to get 10.8 gm of the title compound. Purity by HPLC: 99.59%
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:12]1[N:17]=[N:16][C:15]([CH:18]2[CH2:20][CH2:19]2)=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:22]=2)[CH:13]=1>C1COCC1>[CH:28]1([O:27][C:24]2[CH:25]=[CH:26][C:21]([C:14]3[CH:13]=[C:12]([O:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[N:17]=[N:16][C:15]=3[CH:18]3[CH2:19][CH2:20]3)=[CH:22][CH:23]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN1CCC(O)CC1
Reactant: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CC2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CC3)nn2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1-methyl-piperidin-4-ol (0.50 mmol, 0.06 g) in THF (1 mL) at room temperature was added sodium hydride (60% dispersion in mineral oil) (0.75 mmol, 0.03 g) and continued stirring for 15 min. The reaction mixture was cooled to 0° C. using an ice bath. To this was added a solution of 6-chloro-4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-pyridazine (0.25 mmol, 0.082 g) in THF (0.5 mL). After completion of addition, the reaction mixture was warmed to 50° C. and stirred for 2 hours. After cooling the reaction to room temperature, the reaction was quenched with water (1 mL) and extracted with ethyl acetate (1×5 mL). The ethyl acetate layer was washed with brine (2 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 4 g SiO2 cartridge 4-6% (2N NH3 in MeOH) in DCM to give 4-(4-cyclohexyloxy-phenyl)-3-cyclopropyl-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.030 g). LCMS: m/z 409 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.48-7.58 (2 H, m), 7.30-7.48 (1 H, m), 7.04-7.14 (2 H, m), 5.30-5.54 (1 H, m), 4.37-4.48 (1 H, m), 3.60-3.70 (1 H, m), 3.14-3.51 (3 H, m), 2.93 (3 H, s), 2.54 (1 H, d), 2.41 (1 H, d), 2.16-2.31 (2 H, m), 1.96-2.10 (3 H, m), 1.76-1.89 (2 H, m), 1.27-1.67 (6 H, m), 1.09-1.24 (4 H, m).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: COCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 4-iodophenylsulphonyl chloride (3.64 g, 12 mmol) in DCM (30 ml) was added dropwise to a solution of 2-methoxyethylamine (1.3 ml, 15 mmol) and triethylamine (2 ml, 15 mmol) in DCM (60 ml) cooled by an ice bath to 0° C. The mixture was then allowed to warm to ambient temperature and stirred for 1 hour. The solvent was removed by evaporation and the resulting oil dissolved EtOAc (100 ml) and washed with 1N aqueous citric acid solution (2×100 ml), brine (100 ml) and dried. The volatiles were removed by evaporation to give the title compound (4.1 g, 100%) as a clear oil. NMR 3.12 (2H, q), 3.28 (3H, s), 3.44 (2H, t), 4.90 (1H, t), 7.57 (2H, d), 7.81 (2H, d); m/z: 342.
Reaction SMILES: [C:1]([N:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1.[C:30]([OH:33])(=[O:32])[CH3:31].[H][H]>C(O)C.[Pd]>[CH2:23]([N:20]1[CH2:21][CH2:22][CH:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([N:4]([C:1](=[O:3])[CH3:2])[CH3:5])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:18][CH2:19]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1.[C:30]([OH:33])(=[O:32])[CH3:31].[NH:20]1[CH2:21][CH2:22][CH:17]([NH:16][S:12]([C:9]2[CH:10]=[CH:11][C:6]([N:4]([C:1](=[O:3])[CH3:2])[CH3:5])=[CH:7][CH:8]=2)(=[O:14])=[O:13])[CH2:18][CH2:19]1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCNCC2)cc1
Yield: 100 %

Procedure:
N-(1-Benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide was prepared as a colorless oil from the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (20.0 g, 80.8 mmol) and 4-amino-1-benzylpiperidine (18.16 ml, 88.9 mmol) in a similar manner to that described in Preparative Example 16. This oil was dissolved in ethanol (200 ml), followed by the addition of glacial acetic acid (10.0 ml). The obtained mixture was stirred in the presence of 10% palladium/carbon (water-containing one, 2.00 g) in a hydrogen atmosphere (1 atm) at 50° C. for 5 hours and filtered to remove the catalyst. The filtrate was concentrated to precipitate a crystal. The resulting mixture was washed with ethyl acetate and filtered to give the title compound as a white crystal (29.70 g, overall yield of two steps: 100%). m.p.: 177 to 184
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:38])=[C:34](Cl)[N:35]=3)[C:30](=[O:39])[C:29]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C.N1C=CC=CC=1>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:38])=[C:34]([N:10]4[CH2:11][CH2:12][CH:7]([N:2]5[CH:6]=[CH:5][N:4]=[N:3]5)[CH2:8][CH2:9]4)[N:35]=3)[C:30](=[O:39])[C:29]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: c1cn(C2CCNCC2)nn1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCOC(=O)c1cn(C2CC2)c2nc(N3CCC(n4ccnn4)CC3)c(F)cc2c1=O
Temperature: 100 °C
Yield: 66 %

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (225 mg, 1.2 mmol) and DBU (182 mg, 1.2 mmol) was added to a suspension of ethyl 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (150 mg, 0.48 mmol) in a mixture of acetonitrile (10 ml) and pyridine (3 ml). The reaction mixture was heated at 100° C. for 5 hrs. The suspended solid was filtered and the filtrate was concentrated to dryness. The residue was triturated with water and separated solid was filtered, washed with water and dried to give 135 mg of desired product. m.p. 213°-214° C.; 1H NMR (CDCl3) δ: 8.48 (s, 1H), 8.11 (d, 1H), 7.72 (s, 1H), 7.60 (s, 1H), 4.60-4.85 (m, 3H), 4.29-4.40 (q, 2H), 3.43-3.54 (m, 1H), 3.21-3.35 (m, 2H), 2.10-2.36 (m, 4H), 1.36 (t, 3H), 0.95-1.23 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.[Cu]>[CH2:26]([O:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:11]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=[CH:8][N:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cccnc1Oc1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccnc1Oc1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 46.4 %

Procedure:
Methyl 2-(3-hydroxyphenoxy)-3-pyridinylacetate (0.8 g) and anhydrous potassium carbonate (0.21 g) were stirred together in DMF under nitrogen at 70° C. After 20 minutes benzyl bromide (1.06 g) was added together with copper bronze (cat.) and the reaction mixture heated to 100° C. for 3 hours. GC analysis indicated 50% reaction. A second equivalent of both potassium carbonate and benzyl bromide was added and heating continued at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, filtered, diluted with water and extracted with ether (×3). The ether extracts were combined, dried, filtered and evaporated to give a brown oil. Chromatography on silica gel (eluent petroleum ether - ether, 50:50) afforded methyl 2-(3-benzyloxyphenoxy)-3-pyridinylacetate as a light yellow solid (0.5 g, 46%).