Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].Cl[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[C:7]1([CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]([NH:1][C:20]2[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=2)[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(C(=O)O)C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(NC(C(=O)O)C(c2ccccc2)c2ccccc2)n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 19.2 %

Procedure:
2.60 g (10.8 mmol) of 2-amino-3,3-diphenylpropionic acid and 0.64 g (4.5 mmol) of 2-chloro-4,6-dimethylpyrimidine were introduced into a mixture of 16 ml of DMF and 16 ml of water, 0.57 g (5.4 mmol) of sodium carbonate was added and the mixture was stirred at 80° C. for 24 hours. Then 100 ml of ethyl acetate and a little water were added, and the phases were separated. The aqueous phase was acidified (pH 1-2) with 6 normal hydrochloric acid. The resulting precipitate was filtered off with suction and washed with ethyl acetate, then dried. 0.30 g (19.2%) of a white powder of melting point 172-174° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.[C:14](O)(=[O:16])C.C(O)(=O)C.IC1C=CC=CC=1.C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3]1([O:16][CH3:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[CH:5]=[CH:4]1
Reactant: COc1ccc(O)c2ccccc12
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Ic1ccccc1
Product: COC1(OC)C=CC(=O)c2ccccc21

Procedure:
For example, a solution of 4-methoxynaphthol (16 mmol) and iodobenzene diacetate (6.1 g, 19 mmol) in methanol (75 mL) is stirred at room temperature, under a nitrogen atmosphere for 1 hour. The resultant dark blue solution is poured into a saturated solution of NaHCO3 (75 mL), then evaporated to reduced volume. The blue oil is extracted with CH2Cl2 (3×75 mL) and the organic layer is washed with water (3×75 mL), brine (2×75 mL), and is dried over MgSO4, and filtered and evaporated to dryness (bath temp. <40° C.) to yield the product as a dark blue semi-solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:14]=[C:15]1[C:20]2[S:21][CH:22]=[C:23]([S:24](Cl)(=[O:26])=[O:25])[C:19]=2[CH2:18][CH2:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:24]([C:23]3[C:19]4[CH2:18][CH2:17][CH2:16][C:15](=[O:14])[C:20]=4[S:21][CH:22]=3)(=[O:25])=[O:26])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: O=C1CCCc2c(S(=O)(=O)Cl)csc21
Product: O=C1CCCc2c(S(=O)(=O)N3CCN(c4ccc(F)cc4)CC3)csc21

Procedure:
From 1-(4-fluorophenyl)-piperazine (91 mg) and 7-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-sulfonyl chloride (the compound of Preparation Example 7) (120 mg), the title compound (148 mg) was obtained as a colorless solid, in the same way as Preparation Example 41.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH3:26][C@H:27]1[CH2:32][CH2:31][C@H:30]([NH:33][C:10]([C:2]2[S:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:12])[CH2:29][CH2:28]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1nc2ccccc2s1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2nc3ccccc3s2)CC1
Temperature: 50 °C

Procedure:
A solution of benzothiazole-2-carboxylic acid (359 mg, 2 mmol), and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.525 mL, 3 mmol) were added and the mixture heated at 50° C. for 3 hours. The reaction mixture was cooled, and treated with 10% HCl (15 mL). The solution was extracted with ethyl acetate (15 mL). The ethyl acetate extract was then washed with 10% HCl (15 mL), water (15 mL), and brine (15 mL). Dilution of the remaining solution with ethyl acetate (50 mL) and cooling to −20° C. afforded 25 mg (5%) 412:
Reaction SMILES: [CH2:1]1[O:15][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH2:22]([NH:23][CH2:1][CH:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:1][CH:2]([OH:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NCCCCCCN
Reactant: CCCCCCCCCCCCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-tetradecene oxide (91.8 g.) and hexamethylenediamine (25 g.) and recrystallization of the resulting product (71 g., m.p. 118°-121° C.) from ethanol gave N,N'-(1,6-hexylene)-bis[2-hydroxytetradecylamine] (I: R = CH3 (CH2)11, R' = H, X = (CH2)6, Z = H) (55.3 g., m.p. 122°-126° C.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]([C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)O)[C:11]#[N:12].O=P(Cl)(Cl)[Cl:22]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]([Cl:22])[C:15]1[O:16][CH:17]=[CH:18][CH:19]=1)[C:11]#[N:12]
Reactant: N#CC(=C(O)c1ccco1)c1nc2ccccc2s1
Reactant: O=P(Cl)(Cl)Cl
Product: N#CC(=C(Cl)c1ccco1)c1nc2ccccc2s1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2-Benzothiazol-2-yl-3-furan-2-yl-3-hydroxyacrylonitrile (474 mg, 1.77 mmol) was suspended in POCl3 (5 mL). The suspension was first stirred at 50° C. for 1 hr then refluxed for 30 min until the solid dissolved completely. The resulting brown solution was poured over crushed ice (200 mL). The resulting solids were isolated by filtration, washed with water until the pH of the wash water became neutral, and air-dried to yield 477 mg (94%) of 2-benzothiazol-2-yl-3-chloro-3-furan-2-ylacrylonitrile. MS (m/z, ES+): 287.0 (Cl35M+1, 100%), 289.0 (Cl37M+1, 45%).
Reaction SMILES: C1C(Br)=CC2NC=C(C3N=C(C4C5C=CC(Br)=CC=5NC=4)NC=3)C=2C=1.C1C=CC2NC=C(C3N=C([C:40]4[C:44]5[CH:45]=[CH:46][C:47]([Br:49])=[CH:48][C:43]=5[NH:42][CH:41]=4)NC=3)C=2C=1.C1C=CC2NC=C([C:59]3[N:63]=[C:62]([C:64]([C:66]4[C:70]5[CH:71]=[CH:72][C:73]([OH:75])=[CH:74][C:69]=5[NH:68][CH:67]=4)=[O:65])[NH:61][CH:60]=3)C=2C=1>CCCCCCC.C(OCC)(=O)C.CO.O>[CH:72]1[C:73]([OH:75])=[CH:74][C:69]2[NH:68][CH:67]=[C:66]([C:64]([C:62]3[NH:61][CH:60]=[C:59]([C:40]4[C:44]5[CH:45]=[CH:46][C:47]([Br:49])=[CH:48][C:43]=5[NH:42][CH:41]=4)[N:63]=3)=[O:65])[C:70]=2[CH:71]=1
Reactant: O=C(c1nc(-c2c[nH]c3ccccc23)c[nH]1)c1c[nH]c2cc(O)ccc12
Reactant: Brc1ccc2c(-c3nc(-c4c[nH]c5ccccc45)c[nH]3)c[nH]c2c1
Agent: Brc1ccc2c(-c3c[nH]c(-c4c[nH]c5cc(Br)ccc45)n3)c[nH]c2c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1nc(-c2c[nH]c3cc(Br)ccc23)c[nH]1)c1c[nH]c2cc(O)ccc12

Procedure:
This solid was further fractionated by using centrifugal countercurrent chromatography with two different solvent systems consisting of heptane/ethyl acetate/methanol/water in ratios of 4:7:4:3 and 5:7:4:3. A fraction containing nortopsentin A and a mixture of nortopsentin B and C along with topsentin (400 mg) and bromotopsentin (540 mg) were obtained. Nortopsentin A (250 mg) was purified by HPLC on a Hibar NH2 column (10×250 mm), using 5:1 chloroform/methanol as eluant. Preparative TLC (Kieselgel 60F264, 2 mm thickness, ethyl acetate) afforded a pure nortopsentin C (200 mg) and a fraction containing nortopsentin B. Pure nortopsentin B (250 mg) was finally recrystallized from ethyl acetate/chloroform.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(CC)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1(/[CH:6]=[C:7]2/[C:8](=O)[C:9]3[CH:10]=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[N:13][C:14]=3[CH2:15][CH2:16]/2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24]>C(O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]3[C:8]([C:9]4[CH:10]=[CH:11][C:12]([C:17]([O:19][CH3:20])=[O:18])=[N:13][C:14]=4[CH2:15][CH2:16]3)=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: Cc1cc(NN)ccc1C#N
Reactant: COC(=O)c1ccc2c(n1)CC/C(=C\C1CCCC1)C2=O
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc2c(n1)CCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a dried reaction flask, (E)-methyl 6-(cyclopentylmethylene)-5-oxo-5,6,7,8-tetrahydroquinoline-2-carboxylate (prepared according to the step (1) of Example 1) (0.428 g, 1.50 mmol) and 4-hydrazino-2-methylbenzonitrile hydrochloride (0.287 g, 1.56 mmol) were dissolved in ethanol (20 mL). In the protection from light and under the nitrogen atmosphere, the reaction solution was stirred at 80° C. for 8 hr. The reaction solution was concentrated under a reduced pressure to produce a crude reddish black viscous liquid (0.698 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: COCCCN
Product: COCCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 3-methoxypropylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 160-175° C.; LC-MS: 444 (MH+); HPLC RT: 3.92 minutes.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([O:18]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:22][NH2:23]>C(O)C>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:16]([NH:22][NH2:23])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of Example 1B (2.65 g, 10 mmol) in ethanol (20 mL) was treated with hydrazine hydrate (3.12 mL, 100 mmol), heated to reflux for 18 hours, cooled to room temperature, and filtered. The resulting solid was washed with ethanol and dried under vacuum to provide 1.86 g (74%) of the desired product of sufficient purity for subsequent use.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.CS(CCO)(=O)=[O:13].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:13])[CH:3]=1
Reactant: CS(=O)(=O)CCO
Reactant: N#Cc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Br)cc1O
Temperature: 25 °C

Procedure:
To a stirred solution of 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol) in DMF (20 mL) was added 2-(methylsulfonyl)ethanol (3.7 g, 30 mmol) and then NaH (2.4 g, 60% in mineral, 60 mmol) in portions at 0° C. The mixture was then warmed to rt. and quenched with 1N HCl, and extracted by EtOAc. The organic layers were washed with brine and dried over sodium sulfate, concentrated to give 4-bromo-2-hydroxybenzonitrile. 1H-NMR (400 MHz, DMSO) δ 7.55-7.57 (d, J=8.61 Hz, 1H), 7.16 (s, 1H), 7.11-7.13 (m, 1H).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH2:7][CH2:8][C:9](=[N:10]O)[C:4]=2[CH:3]=[CH:2]1.[OH2:12]>>[S:6]1[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[C:9](=[O:12])[NH:10][CH2:8][CH2:7]1
Reactant: ON=C1CCSc2sccc21
Reactant: O
Product: O=C1NCCSc2sccc21
Reaction time: 0.33 h

Procedure:
To 300 g of polyphosphoric acid warmed at 70° C. was added 19.5 g of 5,6-dihydro-4H-thieno[2,3-b]thiopyran-4-one 4-oxime portionwise with stirring for 20 minutes. The mixture was stirred at 80° C. for 2.5 hours, poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting crude crystals were recrystallized from ethanol to give 10 g of 2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one as white crystals, melting at 195°-196° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3F)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2].Cl.Cl.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([CH2:36][NH2:37])=[C:30]2[CH:29]=[CH:28]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][CH:18]=[N:17][C:16]=3[NH:37][CH2:36][C:35]3[CH:34]=[CH:33][N:32]=[C:31]4[NH:27][CH:28]=[CH:29][C:30]=34)[CH:11]=2)[C:6]([CH3:24])([CH3:23])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: NCc1ccnc2[nH]ccc12
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3F)cc21
Agent: Cl
Product: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)cc21

Procedure:
The titled compound was prepared from N-(1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-fluoro-nicotinamide and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine dihydrochloride by the method described in Step A of Example 1. MS (ES+): 455 (M+H). Calc'd. for C26H26N6O2—454.53.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[N:11]1([C:17](=[O:19])[CH3:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17](=[O:19])[CH3:18])[CH2:12][CH2:13]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 100.5 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (6.7 g, 47.5 mmol), 1-piperazin-1-yl-ethanone (6.7 g, 52.3 mmol) and K2CO3 (6.6 g, 47.5 mmol) in DMSO (60 mL) was heated at 100° C. for 18 h. After cooling, the mixture was poured into H2O (0.5 L). The resulting yellow precipitate was filtered and washed with H2O to afford of 1-[4-(4-nitro-phenyl)-piperazin-1-yl]-ethanone (11.9 g). This was partially dissolved in EtOH (100 mL) and AcOH (50 mL). The mixture was warmed to ca. 65° C. and iron powder (−325 mesh, 12.0 g, 215 mmol) was added in 1-g portions. The mixture was heated at reflux for 2 hr and filtered through a pad of Celite. The filtrate was evaporated to leave a black oil, which was basified by addition of 2 M aq NaOH and was extracted with EtOAc. The combined organics were washed with brine, dried on MgSO4, filtered, and evaporated in vacuo to afford 1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (6.7 g) as a yellow solid. An aliquot of this material (2.0 g, 9.12 mmol) was dissolved in EtOH (5 mL) and HNO3 was added (69% aq soln., 1.26 mL, 19.61 mmol), followed by cyanamide (50% w/v aq soln., 2.48 mL, 31.92 mmol). The resulting mixture was heated at reflux for 18 h. It was cooled to room temperature and poured into Et2O (100 mL). The ethereal layer was separated and concentrated. The resulting precipitate was filtered and washed with iPrOH/Et2O, then neat Et2O. The light brown solid was dried to afford N-[4-(4-acetyl-piperazin-1-yl)-phenyl]-guanidine nitrate (1.2 g). This material (1.1g, 2.84 mmol) was dissolved in 2-methoxyethanol (14 mL) and K2CO3 (0.79 g, 5.68 mmol) was added, followed by 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone (0.60 g, 2.84 mmol). The resulting mixture was heated at 115° C. for 18 h. It was cooled and concentrated. The residue was purified by SiO2 chromatography (9:1 EtOAc/2 M NH3 in MeOH) and recrystallisation from iPr2O/MeOH to afford the title compound (930 mg) as a light brown solid. 1H-NMR (CDCl3), 2.15 (s, 3H, CH3), 2.69 (s, 3H, CH3), 2.71 (s, 3H, CH3), 3.12 (t, 2H, J=5.4 Hz, CH2), 3.15 (t, 2H, J=5.4 Hz, CH2), 3.63 (t, 2H, J=5.4 Hz, CH2), 3.79 (t, 2H, J=5.4 Hz, CH2), 6.90 (d, 1H, J=5.4 Hz, pyrimdinyl-H), 6.96 (m, 2H, Ph-H), 6.98 (br. s, 1H, NH), 7.54 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.4 Hz, pyrimidinyl-H). MS (ESI+) m/z 409.6 (C21H24N6OS requires 408.5).
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.C(=O)(O)[O-].[Na+].[Cl:15][C:16]1[N:21]=[N:20][C:19]([NH2:22])=[CH:18][CH:17]=1>C(O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([CH:8]=[CH:9][N:22]=2)[N:21]=1
Reactant: CCOC(CBr)OCC
Reactant: Nc1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc2nccn2n1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
Bromoacetaldehyde diethylacetal (36.5 g, 216 mmol) was added to a solution of aq.cHBr (7.2 ml) and then heated to reflux for 30 min. The mixture was then cooled to 0° C., upon which ethanol (236 ml), sodium bicarbonate (8.09 g, 95 mmol) and 6-chloropyridazin-3-amine (4 g, 30 mmol) were added. The mixture was heated to 80° C. for 3 h (reaction was monitored by TLC) and then allowed to cool to RT. The mixture was concentrated under reduced pressure, diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh), to afford 6-chloroimidazo[1,2-b]pyridazine (4.0 g, 85.2%,) as Off-white solid. 1H NMR: 200 MHz, CDCl3: δ 7.4-7.2 (Ar, 4H), 3.85 (q, 1H), 3.4 (q, 1H), 3.2 (q, 2H), 1.35 (t, 3H), 1.1 (t, 3H). MS: [M+H]+: m/z=154.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([CH:18]([OH:21])[CH2:19][OH:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.[F-].[K+]>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]>[OH:21][CH:18]([C:15]1[CH:16]=[CH:17][C:10]2[CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]([C:26]4[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=4)[CH:3]=[C:4]3[C:12](=[O:13])[C:11]=2[CH:14]=1)[CH2:19][OH:20]
Reactant: O=c1c2cc(C(O)CO)ccc2ccc2ncc(Cl)cc12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Product: Cn1cc(-c2cnc3ccc4ccc(C(O)CO)cc4c(=O)c3c2)cn1
Temperature: 180 °C

Procedure:
A test tube fitted with a teflon septum was charged with 3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (9 mg, 0.03 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12 mg, 0.060 mmol), Pd2(dba)3 (1 mg, 0.001 mmol), (tBu3)PBF4 (1 mg, 0.003 mmol) and potassium fluoride (6 mg, 0.098 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed DMF (0.9 mL) was added and the reaction was heated in a microwave at 180° C. for 30 min. The reaction was poured into an ethyl acetate/brine mixture and washed twice with brine. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via reverse phase HPLC (10-70% acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 9.00 (d, 1H); 8.58 (d, 1H); 8.27 (s, 1H); 7.91 (s, 1H); 7.81 (s, 1H); 7.75 (d, 1H); 7.61 (d, 1H); 7.38 (d, 1H); 7.24 (d, 1H); 5.0 (dd, 1H); 3.99 (s, 3H); 3.87 (dd, 1H); 3.72 (d, 1H). Hydroxyl/protons were not observed. LRMS (APCI) calc'd for (C20H18N3O3) [M+H]+, 348.1; found 348.1.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[N:19]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.CO.CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)C.COCCOC>[Cl:1][C:2]1[C:3]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[N:19]=2)=[CH:4][C:5]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(I)c(Cl)cn2)CC1
Reactant: CC1(C)OB(c2cccc(F)n2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Temperature: 90 °C

Procedure:
A mixture of trans-N1-(5-chloro-4-iodopyridin-2-yl)cyclohexane-1,4-diamine (from step 1 above, 300 mg, 0.853 mmol), 2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (285 mg, 1.280 mmol), PdCl2(dppf).CH2Cl2 adduct (84 mg, 0.102 mmol), DME (4 ml), Ethanol (1 ml), and 2M sodium carbonate (1.706 ml, 3.41 mmol) reaction mixture was stirred at about 90° C. until done by LCMS. The reaction mixture mixture was cooled, then diluted with 25 ml of ethyl acetate and 10 ml of methanol, filtered, and concentrated to yield a crude solid. The crude solid was dissolved in DMSO, filtered and purified by prep LC. After lyapholization, 200 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 321.0 (MH+), retention time=0.48 min.
Reaction SMILES: F[C:2]1[CH:27]=[CH:26][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([O:24][CH3:25])=[CH:22][N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:4]=2[CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.OCCCC1C2C=C([C:52]([NH2:54])=[O:53])C=CC=2SC=1.COC1C(N2CCNCC2)=NC=NC=1>>[NH2:54][C:52]([C:2]1[CH:27]=[CH:26][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([O:24][CH3:25])=[CH:22][N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:4]=2[CH:3]=1)=[O:53]
Reactant: COc1cncnc1N1CCN(CCCc2csc3ccc(F)cc23)CC1
Reactant: NC(=O)c1ccc2scc(CCCO)c2c1
Agent: COc1cncnc1N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cncnc1N1CCN(CCCc2csc3ccc(C(N)=O)cc23)CC1

Procedure:
The title compound was prepared (0.20 g, 37%, mp 169°-170° C.) in a manner analogous to the preparation of 1-[3-(5-fluorobenzo[b]thien-3-yl)propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (Example 52) by the reaction of 3-(3-hydroxypropyl)benzo[b]thiene-5-carboxamide tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine.