Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)CO>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Yield: 58.9 %

Procedure:
To a solution of p-nitrobenzyl chloride (5.2 g, 10mM) and 3.2 g of triethylamine in 30 ml of ethylene glycol is added a solution of N-methylpiperazine (3 g, 30 mM) in 20 ml of ethylene glycol. After complete addition, the resulting solution is heated to 80° C. under nitrogen for 30 minutes. The reaction mixture is quenched into aqueous 10% sodium carbonate solution and extracted with methylene chloride. The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 4.15 g (59%) of 1-methyl-4-[(4-nitrophenyl)methyl]piperazine.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])=[O:25]>O1CCCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:14](=[O:16])[NH:21][C:22]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:23]=1[C:24](=[O:25])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32])[CH3:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1F
Reaction time: 0.67 h

Procedure:
120 g of carbobenzoxy-L-alanine are dissolved in 800 ml of absolute tetrahydrofuran, treated dropwise while cooling with ice with 70 g of thionyl chloride and stirred for 40 minutes while cooling with ice. There is then rapidly added dropwise thereto a suspension of 100 g (0.38 M) of 2-amino-5-nitro-2'-fluorobenzophenone in 400 ml of absolute tetrahydrofuran and the mixture is stirred at room temperature for 24 hours. The solution obtained is concentrated and the residue is treated with ice and 10% sodium bicarbonate solution and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. The residue is dissolved in a small amount of methylene chloride and treated with ether. There is obtained (S)-benzyl-{1-[[2-(o-fluorobenzoyl)-4-nitrophenyl]carbamoyl]ethyl}carbamate. A further recrystallisation from methylene chloride/ether yields a product which melts at 158°-160° C. and shows a rotation of [α]25D =-23.4° (in methylene chloride; 1%). The mother liquors are purified on a 600 g in silica gel column using methylene chloride as the eluting agent, an additional amount of the aforementioned product being obtained.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CS(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CC#N>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:35]4[N:40]=[CH:39][CH:38]=[CH:37][N:36]=4)[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ncccn1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC#N
Product: O=C(c1csc(C2CCN(c3ncccn3)CC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Temperature: 180 °C
Yield: 22.8 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (0.054 g, 0.16 mmol) was dissolved DMSO (1 mL) and cesium carbonate (0.5 mmol) was added followed by 2-chloropyrimidine (0.18 mmol). The reaction was heated to 180° C. by microwave irradiation for 45 minutes. The reaction mixture was diluted with MeCN (1 mL) and the mixture was filtered to remove any insoluble material. The filtrate was diluted with water and the mixture separated by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound as a pale yellow oil (0.015 g). LCMS m/z 411.25 [M+H]+ RT=12.36 min (Analytical Method 2).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][Cl:1]
Reactant: Sc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
Under nitrogen, N-chlorosuccinimide (5.34 g., 40 mmoles) was slurried in 50 ml. of carbon tetrachloride and the stirred mixture cooled in an ice-water bath. o-Chlorothiophenol (5.76 g., 40 mmoles), dissolved in 25 ml. of carbon tetrachloride, was added dropwise. The ice-water bath was removed and the reaction mixture stirred at room temperature for approximately 16 hours. The reaction was filtered, evaporated to an oil, taken up in hexane, refiltered and reconcentrated to yield o-chlorobenzenesulfenyl chloride (6.8 g., oil).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C@H:11]2[CH2:24][N:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([O:33]C)=[O:32])[C:26]2=[O:35])=[CH:6][C:5]=1[F:36]>C(O)C>[ClH:3].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:16][CH2:15][CH2:14][NH:13][CH2:12][C@H:11]2[CH2:24][N:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([OH:33])=[O:32])[C:26]2=[O:35])=[CH:6][C:5]=1[F:36]
Reactant: COC(=O)c1cccn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: O=C(O)c1cccn(C[C@@H]2CNCCO[C@H]2c2ccc(Cl)c(F)c2)c1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 165.6 %

Procedure:
2 N Aqueous sodium hydroxide solution (8.73 mL) was added to a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-{[3-(methoxycarbonyl)-2-oxopyridin-1(2H)-yl]methyl}-1,4-oxazepane-4-carboxylate (2.88 g) in ethanol (25 mL), and the mixture was stirred at 40° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, and the mixture was extracted with water. The aqueous layer was neutralized with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To a solution of the residue in ethyl acetate (5 mL) was added 4 N hydrogen chloride-ethyl acetate solution (22 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, acetonitrile was added to the residue, and the precipitate was collected by filtration. The obtained solid was dissolved in 10% aqueous acetonitrile (17 mL), and an insoluble material was filtered off. To the mother liquor was added acetonitrile (50 ml), and the mixture was stirred overnight. The obtained crystals were collected by filtration to give the title compound (2.01 g).
Reaction SMILES: [C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16]>ClCCl>[C:1]([C:4]1[C:5]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])[C:6]=2[O:7][C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1c(C)oc2c(N)cccc12
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c(C(C)=O)c(C)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 3-acetyl-7-amino-2-methylbenzo[b]furan (2.4 g) in dichloromethane (30 ml) was added acetic anhydride (1.6 g) dropwise. The solution was stirred at ambient temperature for 1 hour and evaporated in vacuo. Toluene was added to the residue and the solution was evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-acetyl-7-acetylamino-2-methylbenzo[b]furan (2.92 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[S:25]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[S:25]([C:29]1[CH:30]=[C:31]([NH:35][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:17])([F:18])[F:16])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:24])[CH:32]=[CH:33][CH:34]=1)(=[O:27])(=[O:28])[NH2:26]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 528.0 [(M−H)−]; mp 302° C.
Reaction SMILES: [I:1]I.[N+:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:1][C:11]1[CH:12]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of iodine (46.0 g, 0.180 mol) and silver sulfate (56.3 g, 0.180 mol) in anhydrous ethanol (500 mL) was added 4-nitroaniline (25.0 g, 0.180 mol) and the reaction mixture was stirred for 5 h at rt. The resulting yellow solution was filtered and concentrated in vacuo. The resulting residue was dissolved into 400 mL ethyl acetate, washed with 1N sodium hydroxide solution (2×250 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to yield 45.5 (95%) of compound 489A, as a yellow solid. HPLC: 98% at 2.837 min (retention time) (Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.1% trifluoracetic acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 265.08 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CN1CCOCC1>CC#N>[CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:14])[CH3:15])[NH:11][C@@H:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Yield: 25.8 %

Procedure:
L-Leucine benzyl ester (186.65 g, 0.843M), ethyl 2-bromopropionate (153.1 g, 0.846M) and N-methylmorpholine (165 ml, 1.5M) were dissolved in dry CH3CN (800 ml) and refluxed for 12 h. The solvent was removed in vacuo and the residue partitioned between H2O (21) and EtOAc (3×11). The organic phase was washed with brine, dried and evaporated in vacuo. The resulting oil was chromatographed on SiO2 in 7.5% EtOAc in hexane to give the title compound (70 g) as the faster running fraction; (Found: C,67.02; H,8.42; N,4.25; C18H27NO4 requires C,67.26; H,8.47; N,4.36%); νmax film 1730 cm-1 ; δ(CDCl3) 0.88 and 0.9 (each 3H, each d, each J=6.5 Hz, CH(CH3)2) 1.23 (3H,t,J=7 Hz,CH3CH2O), 1.27 (3H,d,J=7 Hz,CH3CH), 1.5 (2H,m,CHCH2), 1.7 (1H, heptet, J=7 Hz, CH(CH3)2), 2.2 (1H, br, s,NH), 3.32 (2 H,m,CHNHCH), 4.10 and 4.12 (each 1H, each q, each J=7 Hz, OCH2CH3), 5.12 (2H,s, OCH2C6H5) and 7.34 (5H,s, C6H5); m/e 322 (100%; [m+1])+, 260 (15), 186 (26) and 112 (28).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:13]=[N+:14]=[N-:15]>C1C=CC=CC=1>[C:1]1([CH3:12])[CH:2]=[CH:3][C:4]([S:7]([C:10]2[NH:15][N:14]=[N:13][N:11]=2)(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=N
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)c2nnn[nH]2)cc1

Procedure:
A mixture of p-toluenesulfonyl cyanide (0.0 g.) and excess hydrazoic acid in 50 ml. of benzene is stirred at room temperature for 20 hours. The product is filtered off, dissolved in ether, filtered through celite and evaporated to a solid which on trituration with benzene has a melting point, 133°-135° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10](N2C=CN=C2)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][CH2:19][N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][NH2:23]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:10]([NH:17][CH2:18][CH2:19][N:20]([CH2:21][CH2:22][NH2:23])[CH2:24][CH2:25][CH3:26])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1
Reactant: CCCN(CCN)CCN
Reactant: Nc1nc(N)c(C(=O)n2ccnc2)nc1Cl
Solvent: C1CCOC1
Product: CCCN(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A mixture of 23.87 g (100.0 mmol) of 1-(3,5-diamino-6-chloropyrazinoyl)imidazole and 58.51 g (300.0 mmol) of N-(2-aminoethyl)-N-propyl-1,2-ethanediamine in 250 ml of tetrahydrofuran was stirred at ambient temperature overnight. The solvent and excess triamine were evaporated and the residue chromatogaphed on silica gel (150 g) using 1.5:98.5 (v/v) methanol: tetrahydrofuran saturated with ammonia gas as eluent. There was obtained 24.64 g (78.0 mmol, 78%) of 3,5-diamino-N-[2-[(2-aminoethyl)propylamino]ethyl]-6-chloropyrazinecarboxamide as a yellow solid; mp 91°-94° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[N+]([O-])([O-])=[O:18].[K+]>OS(O)(=O)=O>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:18])[NH:5]2
Reactant: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a stirred solution of 6-bromo-7-chloro-5-nitroquinoxaline-2(1H)-one (0.025 g, 0.082 mmol, as prepared above) in conc. H2SO4 (0.5 mL) was added KNO3 (0.011 g, 0.11 mmol) and the resulting dark red solution was stirred at room temperature for 65 h. The solution was then cooled in an ice-bath and diluted with ice to a total volume of 5.0 mL. The precipitated solid was filtered, washed with water (2.0 mL) and dried under vacuum to obtain 0.019 g (72%) crude product. It was purified as follows. 0.016 g crude product was taken up in 1N NaOH (1.1 mL). The insoluble solid was centrifuged and the supernatant liquid was acidified with conc. HCl to pH~2. The precipitated solid was filtered, washed with water (1.0 mL), and dried under vacuum to furnish 0.010 g (38%) pure (purity by HPLC>97%) title compound as a cream colored powder; m.p. 338-343° C. (decomposed); 1H NMR (DMSO-d6): δ 7.351 (s, 1H), 12.251 (s overlapped by a br s, 2H); Elemental analysis for C8H3BrClN3O4, calcd: C, 29.98%; H, 0.94%; N, 13.11%, found: C, 29.79; H, 0.77; N, 12.71.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(Cl)c2)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.1 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (786 mg, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.58 g, 0.020 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(3-chloro-phenoxy)-but-2-enoic acid ethyl ester (1.30 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-2-[4-(3-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid methyl ester (530 mg, 33%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:22]Br.O>ClCCl>[Br:22][C:12]1[C:11]([CH3:14])=[CH:10][C:9]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:13]=1
Reactant: BrBr
Reactant: CCCCCCOc1ccc(C)cc1OCCCCCC
Solvent: ClCCl
Solvent: O
Product: CCCCCCOc1cc(C)c(Br)cc1OCCCCCC
Yield: 90.3 %

Procedure:
Next, 91 g (0.31 mol) of the 1,2-di(n-hexyloxy)-4-methylbenzene was dissolved in 270 g of dichloromethane. While cooling in an ice/water bath, 49.7 g (0.31 mol) of bromine was added dropwise at a temperature below 10° C. After the completion of dropwise addition, 200 g of water was added. The organic layer was separated and washed with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was concentrated on a rotary evaporator, yielding 120 g of an oily matter. This was distilled in vacuum (boiling point 180–190° C./0.5 Torr), obtaining 104 g (yield 90%) of 5-bromo-1,2-di(n-hexyloxy)-4-methylbenzene.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[N:20]=3)[N:17]=2)=[CH:8][CH:7]=1)=[O:5].[CH3:46][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[C:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:28][CH2:29][CH2:30]5)=[CH:25][CH:26]=4)[N:20]=3)[N:17]=2)=[CH:8][CH:7]=1)(=[O:5])[CH3:46]
Reactant: CON(C)C(=O)c1ccc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3n2)cc1
Reactant: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(-c2ccc3nc(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)n3n2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
To a solution of tert-butyl {1-[4-(6-{4-[methoxy(methyl)carbamoyl]phenyl}-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-30 (0.25 g, 0.47 mmol) in THF (10 mL) at 0° C. under an argon atmosphere was added methylmagnesium chloride (3 M in THF, 0.40 mL, 1.19 mmol, 2.5 equiv) portionwise through a septum. The resulting mixture was stirred at 0° C. and at room temperature for 5 h. Additional methylmagnesium chloride (3 M in THF, 0.16 mL, 0.48 mmol, 1.0 equiv) was added and the resulting mixture was stirred for 12 h. The resulting mixture was added to a saturated aqueous ammonium chloride solution (25 mL). The aqueous mixture was extracted with EtOAc (3×25 mL). The combined organic phases were dried (Na2SO4 anh.) and concentrated under reduced pressure. The resulting yellow oil (0.23 g) was purified using MPLC (Biotage Isolera; Snap 10 g cartridge, 100% hexane 2.0 min, gradient to 50% hexane/50% EtOAc 2.0 min, 50% hexane/50% EtOAc 2.0 min, gradient to 100% EtOAc 5.0 min, 100% EtOAc 21.0 min) to give tert-butyl (1-{4-[6-(4-acetylphenyl)-3-phenylimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.053 g, 23%):
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19]Cl)[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>C(#N)C>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCCC3)cc12
Yield: 68.6 %

Procedure:
A mixture of 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) (64 mg, 0.16 mmol), potassium carbonate (64 mg, 0.46 mmol) and pyrrolidine (19 μl, 0.24 mmol), in acetonitrile (1.5 ml) was heated in a sealed tube at 100° C. for 18 hours. The yellow suspension was filtered, the solid washed with ethyl acetate and the combined filtrates concentrated to dryness. The residue was purified by silica gel flash chromatography (gradient ethyl acetate/methanol 0-2%) to yield the title compound (49 mg, 71%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>[C:19]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:21][C:16]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:17][CH:18]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)Cc1ccccc1N2
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccc(N3c4ccccc4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
The obtained 9,10-dihydroacridine (11.8 g, 65.2 mmol) and 4-bromobiphenyl (18.2 g, 78.2 mmol) were dissolved in toluene (500 mL). Then, Pd2(dba)3 (1.4 g, 1.3 mmol) was added thereto under a nitrogen atmosphere. Then, NaOBut (9.4 g, 97.8 mmol) was added thereto, and (t-Bu)3P (1.6 ml, 2.6 mmol) was introduced to the resultant solution. The resultant mixture was reflux-stirred for 5 hours. The completion of the reaction was identified by a TLC. After the reaction was completed, the mixture was cooled to room temperature. The resultant solution was poured onto a thin silica pad so as to perform a short chromatography, and then was washed with MC. The filtrate was evaporated under a reduced pressure to remove the solvent. The residue was then purified by silica gel column chromatography (methylene chloride/n-hexane (1/10)) to obtain 10-(biphenyl-4-yl)-9,10-dihydroacridine compound (pale yellow solid, 15.3 g, yield 70%).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=1>C(#N)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:2]([NH:1][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[C:3]([CH:10]=1)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5]
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Reactant: COc1ccc(CO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)N(C)OC)cc1
Temperature: 70 °C
Yield: 74.2 %

Procedure:
A solution of 8 (3.75 g, 17.3 mmol) in 50 mL of acetonitrile was treated with p-toluenesulfonic acid monohydrate. The reaction mixture was heated to 70° C. with stirring. 4-Methoxybenzyl alcohol (2.63 g, 19.0 mmol) in acetonitrile (3 mL) was added dropwise via syringe keeping the reaction temperature at 70° C. The reaction was stirred at 70° C. for 12 h, allowed to cool to ambient temperature, and concentrated in vacuo. Chromatography afforded 9 (4.3 g, 75%) as light yellow solid.