Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCCCC1.C([N-]C(C)C)(C)C.[Li+].[C:15]([O:18]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:17])[CH3:16].[C:38]([O:58][CH:59]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)(=[O:57])/[CH:39]=[CH:40]\[C:41]([O:43][CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42]>C(O)(=O)C.O>[C:15]([CH2:16][CH:40]([CH2:39][C:38]([O:58][CH:59]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)=[O:57])[C:41]([O:43][CH:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:42])([OH:18])=[O:17]
Reactant: CC(=O)OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(/C=C\C(=O)OC(c1ccccc1)c1ccccc1)OC(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: O=C(O)CC(CC(=O)OC(c1ccccc1)c1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 28.9 %

Procedure:
The reaction product obtained by conducting the Michael-addition reaction in the same manner as in Example 116 using 5.7 ml of a 1.5M cyclohexane solution of lithium diisopropylamide, 2.6 g of trityl acetate and 3.2 g of dibenzhydryl maleate, was dissolved in a liquid mixture of 20 ml of acetic acid and 5 ml of water, and the solution was left to stand at room temperature overnight and then evaporated to dryness under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform/methanol=100/1→10/1) to obtain 1.05 g (yield: 29%) of the above-identified compound as white crystalline powder having a melting point of from 105° to 106° C.
Reaction SMILES: [CH3:1][C:2]1[N+:7]([O-])=[C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(OC(=O)C)(=O)C>[C:14]([O:16][CH:9]1[C:6]2=[N:7][C:2]([CH3:1])=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:4]=[C:5]2[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:15])[CH3:3]
Reactant: CCOC(=O)c1cc2c([n+]([O-])c1C)CCCCC2
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc2c(nc1C)C(OC(C)=O)CCCC2
Yield: 82.4 %

Procedure:
Ethyl 2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (1.00 g, 4.02 mmol) was dissolved in acetic anhydride (7.0 ml) and heated under reflux for 1.5 hours. After cooling, excess acetic anhydride was evaporated under reduced pressure, the thus obtained residue was mixed with ice water and saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate, and the resulting organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:1) to obtain the title compound (482.5 mg, 45.8%) as pale brown oil.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][CH2:5][NH:6][C:7]([C@H:9]1[O:13][C@@H:12]([N:14]2[C:18]3[N:19]=[C:20]([C:24]#[C:25][CH2:26][CH:27]4[CH2:32][CH2:31][CH:30]([C:33](OC)=[O:34])[CH2:29][CH2:28]4)[N:21]=[C:22]([NH2:23])[C:17]=3[N:16]=[CH:15]2)[C@H:11]([OH:37])[C@@H:10]1[OH:38])=[O:8]>>[CH2:5]([NH:6][C:7]([CH:9]1[CH:10]([OH:38])[CH:11]([OH:37])[CH:12]([N:14]2[CH:15]=[N:16][C:17]3[C:18]2=[N:19][C:20]([C:24]#[C:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH:30]([C:33](=[O:34])[NH:3][CH2:1][CH3:2])[CH2:29][CH2:28]2)=[N:21][C:22]=3[NH2:23])[O:13]1)=[O:8])[CH3:4]
Reactant: CCN
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(N)nc(C#CCC4CCC(C(=O)OC)CC4)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)C1CCC(CC#Cc2nc(N)c3ncn(C4OC(C(=O)NCC)C(O)C4O)c3n2)CC1
Temperature: 60 °C
Reaction time: 80 h
Yield: 73 %

Procedure:
To a sealed tube containing 5 mL of freshly distilled ethylamine was added 10 mg (0.02 mmol) of ATL146e. The flask was sealed and allowed to stir at 60° C. for 80 hours. After this time the reaction was only about 50% complete by HPLC. The vessel was cooled to 0° C., opened, and the ethylamine was removed in vacuo to yield 4.5 mg (73%) of JR3037 as a white solid and the recovery of 4.0 mg of starting material after the residue was purified by RP-HPLC. 1H NMR (CD3OD-d4) δ. 13C NMR (CD3OD-d4) δ. APCI m/z (rel intensity) 500.8 (MH+, 100), 327.4 (3).
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)C.[C:18]1([CH3:32])[CH:23]=[CH:22][C:21]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1>[Cu]=O>[C:28]1([CH3:31])[CH:29]=[CH:30][C:25]([N:24]([C:8]2[CH:7]=[CH:6][C:5]3[NH:4][C:16]4[C:11]([C:10]=3[CH:9]=2)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:21]2[CH:20]=[CH:19][C:18]([CH3:32])=[CH:23][CH:22]=2)=[CH:26][CH:27]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Agent: O=[Cu]
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc3[nH]c4ccccc4c3c2)cc1
Temperature: 170 °C
Yield: 79.5 %

Procedure:
A mixture of 1.2 g of 9-acetyl-3-bromocarbazole and 1.2 g of di-p-tolylamine were stirred together in 20 ml N,N′-dimethylacetamide. To this was added 0.8 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid was then taken up for further deprotection using 0.6 g KOH with THF (3 ml), methanol (6 ml) and water (6 ml) at reflux temperature. The reaction mixture was then extracted using ethyl acetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene/hexane (½) as eluent, yielded 1.2 g of 3-(N,N-di-p-tolylamino)-9H-carbazole.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:7][CH:2]([CH2:3][CH2:4][CH:5]=[CH2:6])[CH3:1])(=[O:18])=[O:17]
Reactant: C=CCCC(C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of hex-5-en-2-ol (50 g crude, 500 mmole) in dichloromethane was added triethylamine (103 m 5 L, 750 mmol) at room temperature. The reaction mass was cooled to 0° C. and to it was added a solution of methane sulfonyl chloride (50.4 mL, 650 mmol) in DCM over a period of 30 min. The reaction mass was allowed to come to room temperature and stirred for 2 h. The solution was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get crude hex-5-en-2-yl methanesulfonate as light brown oil (73 g, 82%). 1H NMR (400 MHz, CDCl3): δ ppm 5.84-5.80 (m, 1H), 5.10-5.0 (m, 2H), 4.99-4.98 (m, 1H), 3.15 (s, 3H), 2.52-2.09 (m, 2H), 1.75-1.66 (m, 2H), 1.36-1.34 (d, J=6.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[N+:23]([O-])=O)[S:7][C:6]=2[CH:26]=1.Cl.O.O.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH2:23])[S:7][C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(Br)ccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(Br)ccc12
Yield: 40.8 %

Procedure:
In the same manner as in Starting Material Synthesis Example 21 and using ethyl 6-bromo-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (10 g), ethanol (80 ml), 18% hydrochloric acid (80 ml) and tin(II) chloride dihydrate (20.6 g), ethyl 6-bromo-2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (3.8 g) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]#[C:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: C#Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(C#Cc4ccccc4)cc3CC[C@@H]12

Procedure:
A 1 g portion of (4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was reacted with 0.4 mL of phenylacetylene in a process substantially similar to that of Example 281 to obtain the desired title product in pure form. mp 205°-208°; FDMS 329.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4](=[O:9])[C@H:3]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:18](=[O:43])[N:19]([CH3:42])[CH:20]=[C:21]([C:23]3[C:24]([CH3:41])=[C:25]([NH:29][C:30]([C:32]4[S:36][C:35]5[CH2:37][CH2:38][CH2:39][CH2:40][C:34]=5[CH:33]=4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[N:22]=2)=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[C:4](=[O:9])[C@@H:3]1[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[C:18](=[O:43])[N:19]([CH3:42])[CH:20]=[C:21]([C:23]3[C:24]([CH3:41])=[C:25]([NH:29][C:30]([C:32]4[S:36][C:35]5[CH2:37][CH2:38][CH2:39][CH2:40][C:34]=5[CH:33]=4)=[O:31])[CH:26]=[CH:27][CH:28]=3)[N:22]=2)=[CH:14][CH:15]=1
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc([C@@H]3C(=O)N(C)CCN3C)cc2)n1
Solvent: ClC(Cl)Cl
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc([C@H]3C(=O)N(C)CCN3C)cc2)n1

Procedure:
The racemic mixture (12) was subjected to chiral separation on Chiralcel-AD-H (60% isopropanol in heptane, with 0.1% trifluoroacetic acid) to give individual enantiomers at 4.6 minutes (20) ((−) isomer) ([α]D25=−37.8° (c=3.75, CHCl3), mp=181-183° C.) and at 9.2 minutes (19) ((+) isomer) ([α]D25=+38.8° (c=3.57, CHCl3), mp=180-182° C.). Alternatively, the racemic mixture (12) was subjected to chiral separation on Chiralpak AD (75% isopropanol in heptane, at 1 mL/min) and individual enantiomers were collected from 17 to 27 minutes (20) ((−) isomer) and from 27 to 60 minutes (19) ((+) isomer).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:25])[N:9]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:10]([CH3:16])=[N:11]2)=[O:4].[CH3:26][NH:27][CH3:28].C1COCC1.C(=O)([O-])O.[Na+].Cl.CCOCC>CN(C=O)C.C(Cl)Cl.O>[ClH:1].[CH3:26][N:27]([CH3:28])[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:25])[N:9]([CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24])[C:10]([CH3:16])=[N:11]2)=[O:4]
Reactant: Cc1nc2cccc(NC(=O)CCl)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc(NC(=O)CN(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 48 h
Yield: 85 %

Procedure:
To a stirred suspension of 2-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide (0.75 g, 2.1 mmol) in DMF (3 mL), was added dimethylamine in THF (3.6 mL, 2N, 7.2 mmol) at room temperature. After 2 days, sodium hydrogen carbonate (sat, 10 mL) and water (10 mL) were added to the mixture. After 1 hour, the suspension was filtered and washed with water (5 mL) to give a white solid. To the stirred suspension of above solid in methylene chloride (20 mL), was added HCl in ether (2 mL, 2N, 4 mmol) at room temperature. After 18 hours, the suspension was filtered and washed with methylene chloride (2×20 mL) to give 2-dimethylamino-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide hydrogen chloride as a white solid (0.72 g, 85% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, 2.50 min (62.2%) and 2.71 (37.7%); mp: 256-258° C.; 1H NMR (DMSO-d6) δ 2.21-2.28 (m, 1H, CHH), 2.61-2.70 (m, 2H, 2CHH), 2.73 (s, 3H, CH3), 2.88 (s, 6H, 2CH2), 2.93-3.00 (m, 1H, CHH), 4.40 (d, J=4 Hz, 2H, CH2), 5.44 (dd, J=6, 11 Hz, 1H, NCH), 7.45 (dd, J=1, 8 Hz, 1H, Ar), 7.88 (t, J=8 Hz, 1H, Ar), 8.46 (dd, J=1.8 Hz, 1H, Ar), 10.48 (brs, 1H, HCl), 11.11 (s, 1H, NH), 11.50 (brs, 1H, HCl), 11.86 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.57, 23.04, 30.52, 43.16, 56.83, 58.16, 107.98, 116.49, 120.95, 135.94, 138.34, 146.82, 155.92, 162.45 163.75, 169.02, 172.63; LCMS: MH=372; Anal Calcd for C18H21N5O4+1.8HCl+0.5H2O: C, 48.47; H, 5.38; N, 15.70; Cl, 14.31. Found: C, 48.34; H, 5.03; N, 15.39; Cl, 14.03.
Reaction SMILES: [Br:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([O:19][CH3:20])[C:3]=1[O:21][CH3:22].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].[OH-].[K+]>CO>[CH2:23]([N:9]1[CH2:8][CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]2[CH:5]=[C:4]([O:19][CH3:20])[C:3]([O:21][CH3:22])=[C:2]([Br:1])[C:12]=2[CH2:11][CH2:10]1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: COc1cc2c(c(Br)c1OC)CCNCC2c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2c(cc(OC)c(OC)c2Br)C(c2ccccc2)C1

Procedure:
A mixture of 4.9 g of 6-bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, 0.02 ml of n-butyl bromide and 0.02 mol of potassium hydroxide is dissolved in 120 ml of dry methanol and refluxed for 48 hours. The reaction mixture is evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate is washed with water, dried and evaporated to give 3-n-butyl-6-bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][N:13]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN(S(C)(=O)=O)C3)cc1
Reaction time: 4 h
Yield: 40 %

Procedure:
To an 8-mL vial charged with piperidinomethyl polystyrene (3.57 mmol/g, 99.2 mg, 0.354 mmol) and a solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2), 40.0 mg, 0.118 mmol) in 4 mL dichloromethane was added methanesulfonyl chloride (18.2 μL, 0.236 mmol). The reaction mixture was mixed by orbital shaking for 4 h. The solid was removed by filtration. The filtrate was evaporated, and the residue was purified by preparative reversed-phase HPLC to give a solid (19.8 mg, 40%): Rf=0.20 (1:2 EtOAc/hexanes).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl.C(OCC)(=O)C>[C:31]([NH:1][CH2:2][CH:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)(=[O:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Of the compound from Example 22A, 75 mg (0.25 mmol) were introduced in 2.5 ml of dichloromethane together with 60 μl (0.35 mmol) of N,N-diisopropylethylamine and admixed at RT with 21 μl (0.30 mmol) of acetyl chloride. The mixture was stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate and washed in succession twice each with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and then with saturated aqueous sodium chloride solution, dried over sodium sulphate and freed from the solvent on a rotary evaporator. Further drying in an HV gave 88 mg of the title compound (100% of theory).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1)=O>>[CH3:39][C:33]1[C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)=[CH:37][CH:36]=[C:35]([CH3:38])[N:34]=1
Reactant: Cc1ccc(C(=O)CBr)c(C)n1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1ccc(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)c(C)n1

Procedure:
100 mg (0.224 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 83 mg (0.269 mmol) of 2-bromo-1-(2,6-dimethylpyridin-3-yl)ethanone were reacted according to the General Method 3. Yield: 13 mg (10% of theory)
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[N+:16]([O-])=O)=[C:4]([F:22])[CH:3]=1.C([O-])(O)=O.[Na+]>CCO>[Br:1][C:2]1[CH:20]=[C:19]([F:21])[C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:16])=[CH:10][CH:11]=[C:12]([O:14][CH3:15])[CH:13]=2)=[C:4]([F:22])[CH:3]=1
Reactant: COc1ccc([N+](=O)[O-])c(NCc2c(F)cc(Br)cc2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(N)c(NCc2c(F)cc(Br)cc2F)c1
Temperature: 100 °C

Procedure:
To a solution of N-(4-bromo-2,6-difluorobenzyl)-5-methoxy-2-nitroaniline (600 mg, 1.61 mmol) in EtOH (100 mL) was added SnCl22H2O (1.8 g, 8.1 mmol). The mixture was heated at 100° Celsius for 16 h. The mixture was cooled to RT and NaHCO3 (200 mL) was added. The mixture was filtered through celite and the filtrate extracted with EtOAc (3×200 mL). The combine organics were concentrated to dryness to provide the title compound which was used in the next step without further purification. MS (ESI): mass calcd. for C14H13BrF2N2O, 342.02; m/z found, 343.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(Cl)(=O)C.N1C=CC=CC=1>O1CCCC1.C(OCC)C.O>[Br:11][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
A solution of 2-nitro-4-bromoaniline (7.07 g, 32.6 mmol) in dry tetrahydrofuran (33 mL) was cooled to 0° C. and then treated with acetic anhydride (6.66 g, 65.2 mmol). The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. The reaction mixture was stirred at 25° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the presence of only starting material. The reaction mixture was then slowly treated with acetyl chloride (5 mL) and pyridine (5 mL) at 25° C. The resulting orange suspension was stirred at 25° C. for 2 h and then treated with water (50 mL). The organic compound was extracted into ethyl acetate (2×70 mL). The combined extracts were washed with a 3N aqueous hydrochloric acid solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow solid. The yellow solid was treated with diethyl ether (50 mL) and hexanes (50 mL). The solid was collected by filtration and washed with hexanes to afford N-(4-bromo-2-nitro-phenyl)-acetamide (6.82 g, 81%) as a yellow solid: mp 100-102° C.; EI-HRMS m/e calcd for C8H7BrN2O3 (M+) 257.9640, found 257.9641.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH:3]1[C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH3:21][C:3]1([C:15]([O:17][CH3:18])=[O:16])[C:2](=[O:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4]1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1=O
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
A solution of O1-tert-butyl O3-methyl 4-oxopiperidine-1,3-dicarboxylate (1 g, 3.88 mmol) in DMF (100 mL) was cooled to 0° C. followed by portion wise addition of NaH (60% dispersion of mineral oil, 0.16 g, 3.88 mmol). The resulting mixture was stirred at the same temperature for 15 min followed by addition of MeI (0.7 mL, 11.64 mmol) at 0° C. then stirred at rt for 44 h. After completion of reaction (by TLC), water (100 mL) was added and extracted with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the product as a yellow oil (0.9 g). MS: 272.12 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.[ClH:25]>O1CCOCC1.CCOCC>[ClH:25].[ClH:25].[CH3:10][NH:9][C:8](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: CNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
To tert-butyl 4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate (1.90 g, 5.70 mmol) was added Hydrochloric acid solution (17.10 ml, 68.4 mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30 min. The resulting suspension was diluted with Et2O (20 mL), filtered, rinsed with Et2O (3×10 mL), and the resulting solid was dried in vacuo to provide N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (1.70 g, 5.55 mmol, 97% yield) as an off-white, hygroscopic solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3 H) 2.72-2.79 (m, 3 H) 3.05-3.14 (m, 4 H) 3.17-3.28 (m, 4 H) 7.06 (d, J=8.34 Hz, 1 H) 7.64-7.68 (m, 1 H) 7.68-7.70 (m, 1 H) 8.29-8.39 (m, 1 H) 9.36 (br. s., 2 H). ESI-MS: m/z 234.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N=C=NCCCN(C)C)C>ClCCl>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([N:27]4[CH2:28][CH2:29][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25][CH2:26]4)=[O:20])=[CH:22][CH:23]=3)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc2ncc(-c3ccc(C(=O)O)cc3)n2n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)n2n1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
The reaction of the 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoic acid (124 mg, 0.4 mmol), tert-butyl piperazine-1-carboxylate (82 mg, 0.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (84 mg, 0.44 mmol) and dichloromethane (3 mL) was maintained at room temperature overnight. The resulting solution was purified by preparative HPLC (neutral) to afford tert-butyl 4-(4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)benzoyl)piperazine-1-carboxylate (89 mg, 47% yield) as a yellow solid: 1H NMR (METHANOL-d4) δ: 8.20-8.39 (m, J=8.3 Hz, 2H), 7.85 (s, 1H), 7.63 (d, J=9.9 Hz, 1H), 7.48-7.56 (m, 2H), 6.66-6.79 (m, 1H), 4.55 (d, J=12.1 Hz, 1H), 3.82 (br. s., 1H), 3.58-3.73 (m, 1H), 3.35-3.45 (m, 4H), 3.26 (br. s., 1H), 3.17 (d, J=15.2 Hz, 1H), 3.10 (br. s., 1H), 1.92-2.15 (m, 1H), 1.90 (br. s., 1H), 1.72 (quin, J=7.4 Hz, 2H), 1.34-1.57 (m, 14H), 1.01 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 479.3 [(M+H)+, calcd for C26H35N6O3 479.3].