Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:16])[C:14]=1[I:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[CH2:22]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[C:13]([OH:16])[C:14]=1[I:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c(I)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(O)c(I)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% oil, 1.33 g) was added to a mixture of ethyl 3,5-dihydroxy-4-iodobenzoate (5.00 g) and DMF (50 mL), and the resultant mixture was stirred at 0° C. for 30 minutes in a nitrogen atmosphere. Benzyl bromide (2.78 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.94 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[O:21])[CH:10]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C=Nc1ccccc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1F)Nc1cc(Cl)ccc1C(=O)O

Procedure:
2-Amino-4-chlorobenzoic acid (0.3 g), 2-fluorophenylisocyanate (0.2 ml) and triethylamine (0.24 ml) were stirred in toluene (20 ml) for a week. More 2-fluorophenylisocyanate (0.1 ml) was added and stirring continued for another week. The mixture was concentrated to almost dry, water was added and the pH was adjusted to 1 with diluted HCl. Water was decanted and the residue was dissolved in warm 96% EtOH. The pH was adjusted to 1 again with 4N HCl resulting in the precipitation of a solid, which was filtered and dried to give 4-chloro-2-[3-(2-fluoro-phenyl)-ureido]-benzoic acid (0.25 mg). Mp.=195-197° C. 4-Chloro-2-[3-(3-trifluromethyl-phenyl)-ureido]-benzenesulfonamide (Compound 10):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[NH:14])=[CH:4][N:3]=1.[CH:15](OCC)=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][S:11][C:10]2=[N:14][CH:15]=[O:16])=[CH:4][N:3]=1
Reactant: N=C1SCCN1Cc1ccc(Cl)nc1
Reactant: CCOC=O
Product: O=CN=C1SCCN1Cc1ccc(Cl)nc1

Procedure:
A mixture of 3-(2-Chloro-5-pyridinylmethyl)-2-iminothiazolidine (227 mg, 1.1 mmol) and 10 ml of ethyl formate was heated at the boiling point of ethyl formate for 5 hours with stirring. After distilling the excessive ethyl formate off followed by purification by a silica gel column chromatography, the resultant intended solid was washed with diethyl ether. Yield: 32 mg (13%). Melting point: 99-100° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]#[N:11])[CH:8]=1.Br[CH2:13][CH2:14]Br.[Cl-].[NH4+]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[N:6][N:7]([C:9]2([C:10]#[N:11])[CH2:14][CH2:13]2)[CH:8]=1
Reactant: N#CCn1cc(Cl)cn1
Reactant: BrCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: N#CC1(n2cc(Cl)cn2)CC1
Temperature: 10 °C
Yield: 64.7 %

Procedure:
Into a 4-neck 2 L round bottom flask, previously dried with a heat gun under high vacuum, was added dimethylsulfoxide (175 mL). The flask was placed in a 10° C. bath and sodium hydride (60% oil dispersion, 17.0 g, 300 mmol) was added portionwise with stirring under nitrogen. The resulting suspension was stirred for 10 min before a solution of 2-(4-chloro-1H-pyrazol-1-yl)acetonitrile (10.0 g, 70.6 mmol) and 1,2-dibromoethane (18.3 mL, 213 mmol) in dimethylsulfoxide (175 mL) was added dropwise over a period of 30 min. The internal temperature was kept between 13 and 20° C. during the addition process. The reaction mixture was stirred for 5.5 h while keeping the internal temperature at or below 20° C., followed by stirring for an additional 1 h at room temperature. The mixture was cooled to 10° C., and then a saturated aqueous solution of ammonium chloride (600 mL) was slowly added. The mixture was stirred at 10° C. for 15 min, then extracted with ethyl acetate (1000 mL×3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (10-100% dichloromethane in hexanes), and the residue was crystallized from a mixture of hexanes/diethyl ether to afford 1-(4-chloro-1H-pyrazol-1-yl)cyclopropanecarbonitrile (7.654 g). 1H NMR (400 MHz, CDCl3) δ 1.80-1.82 (m, 4H) 7.47 (d, 1H) 7.62 (d, 1H); MS (EI+) (M+) 167; GCMS retention time 1.64 minutes (Method O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:30])C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11]([CH3:12])=[O:30])=[N:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(Br)cc(-c3ccccc3)n2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2c(Br)cc(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Into a Round bottom flask, [A] 5-Bromo-2-methylsulfanyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine (0.30 g, 0.00094 mol) and Methylene chloride (2 mL, 0.03 mol) were added. m-Chloroperbenzoic acid (0.178 g, 0.00103 mol) was added portion wise over 20 minutes. The reaction was stirred at room temperature for one hour. The reaction was partitioned with DCM (200 mL) and saturated NaHCO3 (200 mL). The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give a yellow solid. The solid was washed with hexane to give 5-Bromo-2-methanesulfinyl-7-phenyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (270 mg, 86%). NMR 1H (DSMO-d6)-9.24 (s, 1H), 8.24 (d, 2H, J=7.44 Hz), 7.92 (s, 1H), 7.56 (t, 2H, J=7.93 Hz), 7.47 (t, 1H, J=7.32 Hz), 2.98 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2(O)[CH2:14][CH:13]3[N:15]([C:16]([C:18]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][NH:26][CH:27]=5)[S:20][CH:19]=4)=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(S(F)(F)[F:35])CC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]2([F:35])[CH2:14][CH:13]3[N:15]([C:16]([C:18]4[CH:22]=[C:21]([C:23]5[CH:24]=[N:25][NH:26][CH:27]=5)[S:20][CH:19]=4)=[O:17])[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: O=C(c1csc(-c2cn[nH]c2)c1)N1C2CCC1CC(O)(c1ncccc1Cl)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1csc(-c2cn[nH]c2)c1)N1C2CCC1CC(F)(c1ncccc1Cl)C2
Reaction time: 1 h
Yield: 41 %

Procedure:
[3-(3-Chloro-pyridin-2-yl)-3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-yl]-[5-(1H-pyrazol-4-yl)-thiophen-3-yl]-methanone (0.17 g, 0.41 mmol) in DCM (4 mL) was cooled to −78° C., under nitrogen, DAST (0.216 mL, 1.64 mmol) added and the reaction mixture stirred for 1 hour. Saturated aqueous sodium hydrogen carbonate and DCM were added, the organics separated, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 1-6% methanol/DCM. Then further purified by HPLC on a C18 cartridge, eluting with 5%-98% methanol/water with 0.1% formic acid. The fractions containing the desired product were concentrated under vacuum to give the title compound as a white solid (0.07 g). LCMS m/z 418.9 [M+H]+. R.T.=4.05/4.14 min (Analytical Method 1).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14]([NH2:17])(=[O:16])=[O:15])=[N:3]1.C1([O:24][C:25](=O)[NH:26][C:27]2[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([O:34][CH3:35])[N:28]=2)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[CH3:1][N:2]1[C:6](=[O:7])[O:5][C:4]([C:8]2[C:9]([S:14]([NH:17][C:25]([NH:26][C:27]3[N:32]=[C:31]([CH3:33])[N:30]=[C:29]([O:34][CH3:35])[N:28]=3)=[O:24])(=[O:16])=[O:15])=[CH:10][CH2:11][CH2:12][CH:13]=2)=[N:3]1
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Reactant: Cn1nc(-c2ccccc2S(N)(=O)=O)oc1=O
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)C2=CCCC=C2c2nn(C)c(=O)o2)n1
Yield: 45.2 %

Procedure:
By the procedure of Example 5, 0.4 g of the product of Example 4 was reacted with 0.41 g of phenyl(4-methyl-6-methoxy-1,3,5-triazin-2-yl)carbamate and 0.24 g of "DBU" in 10 ml of p-dioxane. The isolated crude solid was purified by slurry-washing with 10 ml of warm acetonitrile to yield 0.3 g of the subject compound; m.p. 198°-200° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]([O:11][CH3:12])[O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[F:13].C([Li])CCC.[CH:19](N1CCOCC1)=[O:20].[Cl-].[NH4+]>O1CCCC1.CCCCCC.O>[CH3:10][O:9][CH:8]([O:11][CH3:12])[C:6]1[CH:5]=[CH:4][C:3]([F:13])=[C:2]([CH:7]=1)[CH:19]=[O:20]
Reactant: O=CN1CCOCC1
Reactant: COC(OC)c1ccc(F)c(Br)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(OC)c1ccc(F)c(C=O)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
6.2 g of 2-Bromo-4-dimethoxymethyl-1-fluorobenzene was dissolved in 65 ml of tetrahydrofuran, and the solution was cooled to −60° C. under a nitrogen gas flow. 18 ml of 1.6M n-Butyl lithium in hexane was added dropwise and the mixture was stirred at −60° C. for 1 hour. 3.3 ml of N-Formylmorpholine was added thereto, and the reaction mixture was allowed to warm to room temperature. The mixture was stirred for 1 hour, then ice-cooled, and treated with water and ammonium chloride solution, then extracted with ethylacetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography, to give 2.8 g of the title compound (8% ethyl acetate-hexane).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:15])/[C:5](=[N:13]/[CH3:14])/[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([O:10][C:8]([C:7]1[S:6]/[C:5](=[N:13]\[CH3:14])/[N:4]([CH3:15])[C:3]=1[CH2:2][NH:16][CH:17]1[CH2:18][CH2:19][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:21][CH2:22]1)=[O:9])[CH3:12]
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)c1s/c(=N\C)n(C)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1s/c(=N\C)n(C)c1CNC1CCN(C(=O)OCc2ccccc2)CC1
Yield: 67.8 %

Procedure:
Ethyl (2Z)-4-bromomethyl-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylate (3.0 g) obtained in Example 13) as a synthetic intermediate and benzyl 4-aminopiperidine-1-carboxylate (3.3 g) were dissolved in DMF (50 mL). Potassium carbonate (3.8 g) was added thereto, and the mixture was mixed at 70° C. for 4 hours. The solvent was distilled off, and the residue was poured into water. The mixture was then extracted with a mixed solution of chloroform-methanol, and the extract was dried over anhydrous magnesium sulfate. The solvent-was distilled off, and the residue was purified with a silica gel column to give the title compound (3.1 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:7]1[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=2[C:9]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[CH:8]1)[CH2:5][CH3:6].C(=O)([O-])[O-:26].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][CH2:3][CH:4]([N:7]1[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=2[C:9]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:26])=[CH:23][CH:24]=2)=[CH:8]1)[CH2:5][CH3:6]
Reactant: CCC(COC)n1cc(-c2ccc(C#N)cc2)c2c(=O)[nH]ccc21
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(COC)n1cc(-c2ccc(C(N)=O)cc2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 4-(1-(1-methoxybutan-2-yl)-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)benzonitrile (20.0 mg) obtained in Example 24 in DMSO (0.5 mL) was added potassium carbonate (10.3 mg) at 0° C., 30% aqueous hydrogen peroxide (0.019 mL) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (18.1 mg).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63]/[C:64](/[NH2:67])=[N:65]/O)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]>CN(C=O)C>[CH3:44][N:45]1[C:54]2[C:49](=[CH:50][N:51]=[C:52]([CH3:55])[CH:53]=2)[CH:48]=[C:47]([C:56]2[CH:57]=[C:58]([NH:63][C:64]3[N:65]=[C:6]([C:3]4([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]4)[O:7][N:67]=3)[CH:59]=[CH:60][C:61]=2[CH3:62])[C:46]1=[O:68]
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(O)C1(C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(C(F)(F)F)CC4)n3)ccc1C)c(=O)n2C
Temperature: 100 °C

Procedure:
To a solution of 1-(trifluoromethyl)cyclopropanecarboxylic acid (9 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 1,7-dimethyl-3-(2-methyl-5-(5-(1-(trifluoromethyl)cyclopropyl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A58). MS m/z 456.6 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:27][C@@:25]3([CH3:26])[C@H:21]([CH2:22][CH2:23][C@:24]3([OH:35])[CH2:28][C:29]#[C:30][Si](C)(C)C)[C@H:20]3[C:11]2=[C:12]2[C:17]([CH2:18][CH2:19]3)=[CH:16][C:15](=[O:36])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:27][C@@:25]3([CH3:26])[C@H:21]([CH2:22][CH2:23][C@:24]3([OH:35])[CH2:28][C:29]#[CH:30])[C@H:20]3[C:11]2=[C:12]2[C:17]([CH2:18][CH2:19]3)=[CH:16][C:15](=[O:36])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc([C@H]2C[C@@]3(C)[C@H](CC[C@]3(O)CC#C[Si](C)(C)C)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC[C@@]1(O)CC[C@@H]2[C@@H]3CCC4=CC(=O)CCC4=C3[C@@H](c3ccc(C(C)=O)cc3)C[C@@]21C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.6 %

Procedure:
470 mg of 11beta-(4-Acetylphenyl)-17alpha-hydroxy-17-(3-trimethysilyl-2-propinyl)-14beta-estra-4,9-dien-3-one in 24 ml of tetrahydrofuran is mixed with 2.35 ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and stirred for 5 minutes at room temperature. It is poured on water and extracted with ethyl acetate. The combined organic phases are washed with water, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed with a mixture of hexane/ethyl acetate on silica gel. 280 mg of the title compound is isolated as foam.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[N:25]1([C:31]([NH2:33])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(O)C>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CCN(CC)CC>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3([CH2:22][N:28]4[CH2:29][CH2:30][N:25]([C:31]([NH2:33])=[O:32])[CH2:26][CH2:27]4)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: NC(=O)N1CCNCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (317 mg, 1 mmol), piperazine-1-carboxylic acid amide hydrochloride (273 mg, 1.65 mmol), absolute ethanol (12.7 ml), activated 3 Å molecular sieves (320 mg), Et3N (0.278 ml), titanium (IV) isopropoxide (1.46 ml, 5.20 mmol) and STAB (1.8 g, 8.5 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a off white solid (70 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 2H), 6.86 (d, 2H), 4.30 (br s, 2H), 4.02 (t, 2H), 3.80-3.71 (m, 2H), 3.58-3.48 (m, 2H), 3.23-3.15 (m, 4H), 2.63 (t, 2H), 2.53 (br s, 4H), 2.40 (s, 2H), 2.19-1.73 (m, 14H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>CS(C)=O>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([NH:7][C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([NH2:8])[CH:2]=2)=[N:11][CH:12]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)nc1
Reactant: Nc1cccc(N)c1
Solvent: CS(C)=O
Product: Nc1cccc(Nc2ccc([N+](=O)[O-])cn2)c1
Temperature: 80 °C

Procedure:
m-Phenylenediamine (2.8 mmol, 0.30 g) and 2-fluoro-5-nitropyridine (0.92 mmol, 0.13 g) were dissolved in 6 mL of DMSO. The solution was heated to 80° C. for 18 hours. The solution eventually turned dark red. The reaction mixture was cooled to room temperature and purified directly by flash column chromatography (silica, EtOAc:Hexanes=1:3) to give N1-(5-nitropyridin-2-yl)benzene-1,3-diamine as a reddish crystalline compound (0.19 g, 89% yield): 1H NMR (500 MHz, CDCl3) δ 9.08 (d, 1H, J=2.5 Hz), 8.24 (dd, 1H, J1=2.5 Hz, J2=9.5 Hz), 7.281 (s, 1H), 7.19 (t, 1H, J=8.0 Hz), 6.82 (d, 1H, J=9.5 Hz), 6.74 (s, 1H), 6.70 (d, 1H, J=8.0 Hz), 6.56 (d, 1H, J=7.5 Hz), 3.80 (br, 2H); 13C NMR (125 MHz, CDCl3) δ 159.91, 148.05, 146.93, 139.09, 137.15, 133.59, 130.77, 112.80, 112.66, 109.13, 106.67. The nitro compound (0.43 mmol, 0.10 g) and 10% Pd/C (10 mg) were added to a 20 mL test tube equipped with a stir bar, dry ice (0.5 g) was added to the mixture just before MeOH (7 mL) was added. The suspension was then put into a pressure vessel under 80 psi of H2. The reaction mixture was stirred for 2 hours. The solution turned from yellow to colorless. The reaction mixture was transferred into a 10 mL syringe and filtered through an Acrodisc syringe Filter into a 100 mL round bottom flask containing 37% aqueous HCl (3 mL). The solvent was then evaporated and azeotroped to dryness with toluene and absolute ethanol (3×30 mL of 1:1 mixture). The product was obtained as a grayish yellow powder in quantitative yield. B. Primary Intermediates of Formula (5)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=1>C(#N)C>[I:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][CH2:15][CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[CH3:1])=[CH:20][CH:21]=1
Reactant: ClCCCCOc1ccc(I)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 9 h
Yield: 89 %

Procedure:
To a suspension of (2R)-2-methylpyrrolidine (0.8 g) and cesium carbonate (1.7 g) in acetonitrile (5 mL), 1-(4-chlorobutoxy)-4-iodobenzene obtained in Example 61-(1) (1.4 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (1.4 g, 89%) as a colorless oil.
Reaction SMILES: O1CCCCC1[N:7]1[C:12](=[O:13])[CH:11]=[C:10]([O:14][CH2:15][C:16]2[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[CH:9]=[N:8]1.Cl>CO.CCOCC>[F:25][C:22]([F:23])([F:24])[C:19]1[N:18]=[CH:17][C:16]([CH2:15][O:14][C:10]2[CH:9]=[N:8][NH:7][C:12](=[O:13])[CH:11]=2)=[CH:21][CH:20]=1
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cnn1C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cn[nH]1
Reaction time: 0.25 h
Yield: 67.6 %

Procedure:
2-(Tetrahydro-2H-pyran-2-yl)-5-((6-(trifluoromethyl)pyridin-3-yl)methoxy)pyridazin-3(2H)-one (5.25 g, 12 mmol estimated) was stirred in MeOH (10 mL), and 2 N HCl in Et2O (50 mL) was added. After 16H, the mixture was diluted with Et2O (100 mL), and the solid was filtered off. The solid was stirred in NaHCO3 solution (15 mL) for 15 minutes and then refiltered to provide the title compound (2.2 g, 67%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H), 8.78 (s, 1H), 8.20-8.16 (dd, J=8.1, 1.5 Hz, 1H), 8.00 (d, J=8.1 Hz, 1H), 7.76 (d, J=2.6 Hz, 1H), 6.31 (s, 1H), 5.25 (s, 2H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH3:16].Cl>[OH-].[Na+]>[CH3:14][N:15]([CH3:16])[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(C)c1ccc([N+](=O)[O-])cc1C(=O)O
Yield: 57 %

Procedure:
2-Chloro-5-nitrobenzoic acid (2 g, 9.9 mmol) was dissolved in of 8% sodium hydroxide solution (10 ml) at room temperature. 40% dimethyl amine aqueous solution (1.5 eq) was added and the reaction mixture was heated to reflux for 3 days. The reaction mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and evaporated and the residue crystallized with ether/pet ether to give 2-dimethylamino-5-nitro-benzoic acid (1.14 g, 57%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:10]1=[O:22].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:10]1=[O:22])(=[O:26])=[O:25]
Reactant: Cc1ccc(CN2CC[C@H](O)C2=O)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 107.3 %

Procedure:
Triethylamine (0.51 ml, 3.6 mmol) was added to a cooled solution of (S)-3-hydroxy-1-(4-methylbenzyl)pyrrolidin-2-one (0.5 g, 2.4 mmol) in anhydrous DCM (12.2 ml) at 0° C. under a nitrogen atmosphere. Methanesulfonyl chloride (0.2 ml, 2.6 mmol) was then added dropwise and the reaction was allowed to stir at 0° C. for 15 min before quenching with a satd. sodium bicarbonate solution (10 mL). The mixture was allowed to warm to rt and the aqueous layer was separated and extracted with DCM (2×). The combined oranic layers were dried over MgSO4 and evaporated in vacuo to give a white solid (0.73 g) which was then purified by silica gel chromatography (40 g of silica) eluting with a gradient of 0% to 50% ethyl acetate in hexanes to provide 0.63 g (91%) of the desired product as a white solid.