Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.[N:60]1([S:66](Cl)(=[O:68])=[O:67])[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([F:59])=[C:54]([NH:55][S:66]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)(=[O:68])=[O:67])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)N1CCOCC1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-fluoroaniline (150 mg, 0.383 mmol) and 4-morpholinesulfonyl chloride (142 mg, 0.766 mmol) the title compound of Step A was obtained as a yellow foam (96 mg, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78-10.01 (m, 1H), 8.34 (d, J=5.5 Hz, 1H), 7.58 (td, J=7.4, 2.4 Hz, 1H), 7.17-7.41 (m, 2H), 6.57-6.68 (m, 1H), 3.68 (t, J=4.7 Hz, 4H), 3.42-3.63 (m, 8H), 2.91-3.11 (m, 4H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]=O)[CH3:3].P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:26](CCC)([O-])=O.[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][N:2]([CH2:4][CH:5]1[CH2:7][CH:6]1[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[C:17]#[N:26])[CH3:3]
Reactant: CN(C)CC1CC1c1ccc2[nH]cc(C=O)c2c1
Reactant: CCC[N+](=O)[O-]
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CN(C)CC1CC1c1ccc2[nH]cc(C#N)c2c1
Yield: 75.9 %

Procedure:
In 5 mL of acetic acid was combined 120 mg of crude N,N-dimethyl-2-(3-formyl-indol-5-yl)cycloprop-1-yl-methylamine, ammonium hydrogen phosphate (0.48 g, 3.62 mmol, 7.3 equiv.), and nitropropane (0.04 mL, 0.5 mmol, 1 equiv.). The mixture was stirred and heated to a gentle reflux for 16 h. Water was added after cooling reaction to room temperature, and the mixture was made basic by the addition of 1 N NaOH. The mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give N,N-dimethyl-2-(3-cyanoindol-5-yl)cycloprop-1-yl methylamine (90 mg, 75%) as a brown oil. The oil was purified by flash chromatography to give a brown solid with 92% purity by reverse-phase HPLC. 1H NMR (MeOH-d4): δ 7.88 (s, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.04 (dd, J=8.5, 1.7 Hz, 1H), 2.62 (dd, J=7.3 Hz, 1H), 2.42 (m, 1H), 2.38 (s, 6H), 1.89 (m, 1H), 1.20 (m, 1H), 1.08 (m, 1H), and 0.90 (m, 1H). IR: 2214.5 cm−1. FIMS: 238.2 (M−H)−.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([CH:13]([CH3:21])[C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[S:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[C:5]([CH:13]([CH3:21])[C:14]([NH:16][CH2:17][C:18]([Cl:3])=[O:19])=[S:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C(=O)c1ccccc1)C(=S)NCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(C(=O)c1ccccc1)C(=S)NCC(=O)Cl
Temperature: 25 °C

Procedure:
Thionyl chloride (10 g) is added to N-(α-benzoylthiopropionyl)-glycine (5.4 g) suspended in benzene (25 ml), with stirring. The reaction mixture is maintained at room temperature until all the solid has dissolved. The resulting yellow solution is evaporated in vacuo, taken up into benzene and again evaporated until all the remaining thionyl chloride has been removed. The residual oil is dissolved in 15 ml anhydrous chloroform.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([S:27][C:28]3[N:32]5[N:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]5=[N:30][N:29]=3)=[CH:22][CH:21]=4)[CH:14]=[N:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH:8]1[CH2:9][CH:10]([N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][C:23]([S:27][C:28]3[N:32]5[N:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]5=[N:30][N:29]=3)=[CH:22][CH:21]=4)[CH:14]=[N:13]2)[CH2:11]1
Reactant: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C6CN(C(=O)OC(C)(C)C)C6)c5)cc4c3)n2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nnc(Sc3ccc4ncc(-c5cnn(C6CNC6)c5)cc4c3)n2n1
Reaction time: 2 h

Procedure:
To 3-{4-[6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinolin-3-yl]-pyrazol-1-yl}-azetidine-1-carboxylic acid tert-butyl ester (65 mg, 0.126 mmol) was added 6 mL of (1:1) TFA:dichloromethane. The mixture was allowed to sit for 2 hours. The volatiles were removed by rotary evaporation and then methanol (6 mL) and MP-carbonate (500 mg, 3.18 mmol/g) were added. The resin was filtered and the volatiles were removed in vacuo to provide 3-(1-azetidin-3-yl-1H-pyrazol-4-yl)-6-(6-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl)-quinoline as a yellow solid (quantitative yield).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]=[C:12]1[NH:17][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:15][C:14]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)=[C:13]1[CH:31]([CH2:36][CH2:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33].[CH2:39](I)[CH3:40].[Cl-].[NH4+]>CN(C=O)C>[CH2:39]([N:17]1[C:12](=[O:11])[C:13]([CH:31]([CH2:36][CH2:37][CH3:38])[C:32]([O:34][CH3:35])=[O:33])=[C:14]([C:24]2[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=2)[N:15]=[C:16]1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:40]
Reactant: CCI
Reactant: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)[nH]c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(-c2ccc(C)cc2)nc(N2CCCCC2)n(CC)c1=O
Reaction time: 0.08 h

Procedure:
LHMDS (1M in THF; 2 eq) is added to a cold (−10° C.) stirred solution of methyl 2-(6-oxo-2-(piperidin-1-yl)-4-p-tolyl-1,6-dihydropyrimidin-5-yl)pentanoate (1 eq) in dry DMF (2 mL/mmol of the limiting reagent). After stirring for 5 minutes, ethyl iodide (2 eq) is added and the reaction mixture is stirred at room temperature for 18 hours. A saturated solution of ammonium chloride is then added and the aqueous layer is extracted with ethyl acetate. The organic layer is dried over magnesium sulphate, filtered and evaporated to dryness. The crude material is purified by flash chromatography on silica gel to provide the methyl 2-(1-ethyl-6-oxo-2-(piperidin-1-yl)-4-p-tolyl-1,6-dihydropyrimidin-5-yl)pentanoate which is deprotected following general method D yielding to the title compound.
Reaction SMILES: CS(O[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[NH:31]1[CH2:34][CH2:33][CH2:32]1>C(OCC)C>[N:31]1([C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:7]2)[CH2:34][CH2:33][CH2:32]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Brc1ccc2nc(N3CCC[C@@H](N4CCC4)C3)sc2c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
One equivalent of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10, 0.078 g, 0.2 mmol) and two equivalents of potassium carbonate (55.3 mg, 0.40 mmol) were weighed into a 2.5 mL Biotage microwave vial equipped with a magnetic stirbar. Acetonitrile (1 mL) was added, then 6 equivalents of azetidine (68.5 mg, 1.2 mmol) was weighed into the reaction mixture. The vial was sealed with a septum cap and the reaction mixture was stirred at 80° C. for 72 hours. The reaction mixture was transferred to a 100 mL round bottom flask (methanol rinse). Volatiles were removed under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil. The oil was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF10-4g, 100% dichloromethane to 98:2 dichloromethane/2 M NH3 in methanol). Fractions containing product were combined and concentrated under reduced pressure to give an oil that was dissolved in diethyl ether and dried (MgSO4). The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to give a semi-solid that was triturated with diethyl ether/hexane to give (R)-2-(3-(azetidin-1-yl)piperidin-1-yl)-6-bromobenzo[d]thiazole as a solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.23-1.38 (m, 1H), 1.53-1.69 (m, 1H), 1.80-1.96 (m, 2H), 2.11 (pentet, J=7 Hz, 2H), 2.32-2.43 (m, 1H), 2.93-3.02 (m, 1H), 3.22-3.38 (m, 5H), 3.79 (dt, J=4, 13 Hz, 1H), 3.96 (dd, J=4, 13 Hz, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 352 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:36]=[C:35]3[C:30]([C:31]([NH2:37])=[N:32][CH:33]=[N:34]3)=[CH:29][CH:28]=2)[CH:21]([C:38]([O:40][CH3:41])=[O:39])[CH2:20]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:41][O:40][C:38]([CH:21]1[CH2:20][N:19]([CH2:18][C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[CH2:24][C:23](=[O:25])[N:22]1[CH2:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31]([NH2:37])=[N:32][CH:33]=[N:34]2)=[CH:29][CH:28]=1)=[O:39]
Reactant: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3[nH]2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Reaction time: 4 h
Yield: 69.6 %

Procedure:
To a solution containing (±)-2-[4-(4-amino-quinazolin-7-ylmethyl)-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl]-5-chloro-indole-1-carboxylic acid tert-butyl ester (26 mg, 0.03 mmol) in CH2Cl2 (4 mL) is added trifluoroacetic acid (1 mL) at ambient temperature. After 4 h, the reaction mixture is concentrated in vacuo and then dissolved in water/CH3CN and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 10 mg (47%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ2.62 (m, 1H), 3.05-3.51 (m, 4H), 3.59 (s, 3H), 3.81 (d, J=14.0 Hz, 1H), 4.26 (m, 1H), 4.69 (ABq, ΔAB=310 Hz, JAB=16.4 Hz, 2H), 6.26 (s, 1H), 7.02 (dd, J=8.6, 2.0 Hz, 1H), 7.31 (d, J=8.6 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.52 (s, 1H), 7.61 (d, J=8.7 Hz, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.47 (s, 1H), 8.77 (s, 1H), 9.69 (br s, 2H), 11.17 (s, 1H) ppm; MS (ion spray): m/z 479 (M+H).
Reaction SMILES: C[C@H]([NH2+]C)[C@H](O)C1C=CC=CC=1.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[O:20][CH2:19][CH2:18][C@@:17]2([NH:27][C:28]([NH2:30])=[O:29])[C:24](O)=[O:25].C(O)(=O)C.CO>C(O)C>[F:13][C:14]1[CH:15]=[C:16]2[C@:17]3([C:24](=[O:25])[NH:30][C:28](=[O:29])[NH:27]3)[CH2:18][CH2:19][O:20][C:21]2=[CH:22][CH:23]=1
Reactant: NC(=O)N[C@@]1(C(=O)O)CCOc2ccc(F)cc21
Agent: C[NH2+][C@@H](C)[C@H](O)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NC(=O)[C@@]2(CCOc3ccc(F)cc32)N1
Temperature: 95 °C

Procedure:
A mixture of 9.6 g of the (1R,2S)-ephedrine salt of (S)-6-fluoro-4-ureidochroman-4-carboxylic acid and 68 ml of glacial acetic acid was heated at 95° C. for 1 hour, and then it was evaporated in vacuo at 60° C. This afforded 20 g of an oily residue which was diluted with 50 ml of water at 60° C. and then 50 ml of water at 10° C. The resulting slurry was adjusted to pH 4.5 with 4N sodium hydroxide and the solid was recovered by filtration to give 4.7 g of crude title product, mp 234°-240° C., [alpha]D25 =+50.5° (c=1, methanol). This crude product (4.0 g) was dissolved in 60 ml of boiling absolute ethanol, and the ethanol solution was filtered and cooled to 24° C. The solid was recovered by filtration, to give 2.0 g of (S)(+)-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione, mp 240.5-243.0, [alpha]D25 =+55.4° (c=1, methanol).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].C1(C)C=CC=CC=1.C(O)CCC>C(O[Ti](OCCCC)(OCCCC)OCCCC)CCC.O>[CH3:11][CH2:10][N:12]([C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)=[O:9])[CH2:13][CH3:14]
Reactant: O=C(O)c1cccnc1
Reactant: CCNCC
Agent: CCCCO[Ti](OCCCC)(OCCCC)OCCCC
Solvent: CCCCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1cccnc1

Procedure:
Nicotinic acid (0.5 mole), diethylamine (0.5 mole), toluene (35 ml), n-butanol (60 ml) and tetra n-butoxy titanium were heated until all water was removed by azeotropic distillation from the reaction mixture. The volatile solvents were then distilled off and the remaining product fractionally distilled under vacuum to give nikethamide identified both by its boiling point and its infra-red spectrum.
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:10])[C:6](OC)=[O:7])[CH3:2].O.[NH2:12][NH2:13]>C(O)C>[CH2:1]([O:3][NH:4][C:5](=[O:10])[C:6]([NH:12][NH2:13])=[O:7])[CH3:2]
Reactant: NN
Reactant: CCONC(=O)C(=O)OC
Solvent: CCO
Solvent: O
Product: CCONC(=O)C(=O)NN
Temperature: 65 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 234 g (1.59 mol) of methyl (ethoxyamino)-oxoacetate in 450 ml of ethanol was added to a solution of 92.8 g (1.855 mol) of hydrazine hydrate in 300 ml of ethanol and the mixture was stirred for 2 hours at 65° C. The mixture was cooled to +10° C., the precipitate was suction filtered, washed with a small amount of cold ethanol, and dried. There was obtained 150 g (64.2% of theory) of 1-(ethoxyamino)-2-(hydrazino)-ethane-1,2-dione as white crystals of m.p. 182° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:12][C:13]3[C:14]([F:24])=[C:15]([CH:21]=[CH:22][CH:23]=3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.N[C@@H]1CCCC[C@H]1N.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:12][C:13]3[C:14]([F:24])=[C:15]([CH:21]=[CH:22][CH:23]=3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7][N:8]2[C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:4][CH:3]=1
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1cccc(Sc2c[nH]c3c(F)c(Cl)ccc23)c1F
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Sc2cn(-c3cccnc3)c3c(F)c(Cl)ccc23)c1F
Temperature: 140 °C
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
To a stirred solution of compound 2 (200 mg, 0.54 mmol) in toluene (5 mL) were added 3-bromopyridine (131 mg, 0.81 mmol), trans-1,2-diaminocyclohexane (24.8 mg, 0.21 mmol), K3PO4 (288 mg, 1.35 mmol), Cu(I)I (10.3 mg, 0.05 mmol) at RT under inert atmosphere. The mixture was purged with argon for 15 min and heated to 140° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, added n-hexane (6 mL), stirred for 5 minutes and then filtered. The filtrate was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water and brine solution, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel; 10-12% EtOAc/Hexanes) to afford compound 3 (130 mg, 54%) as an off-white solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1.C(Cl)CCl.CCN(CC)CC>C(Cl)Cl>[CH:9]1([C:12]([O:1][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])=[O:13])[CH2:11][CH2:10]1
Reactant: O=C(O)C1CC1
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(ON1C(=O)CCC1=O)C1CC1

Procedure:
1-Hydroxypyrrolidine-2,5-dione (1.18 g, 10.3 mmol), cyclopropanecarboxylic acid (1.01 ml, 10 mmol), EDC (2.01 g, 10.5 mmol) and Et3N (2.8 mmol, 20 mmol) in DCM were stirred at rt for 5 h before it was partitioned with saturated NH4Cl solution. The organic layer was washed with brine and dried over Na2SO4. After filtration and concentration, 2,5-dioxopyrrolidin-1-yl cyclopropanecarboxylate 24 was isolated and used without further purification.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)=[O:3].[NH2:20][C:21]1[C:22]([OH:31])=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25]>ClCCl>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][CH:4]([C:2](=[O:3])[NH:20][C:21]2[CH:30]=[CH:29][CH:28]=[C:23]([C:24]([O:26][CH3:27])=[O:25])[C:22]=2[OH:31])[CH2:5]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Product: COC(=O)c1cccc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Benzyl 3-(chlorocarbonyl)piperidine-1-carboxylate (500 mg, 3 mmol) and methyl 3-amino-2-hydroxybenzoate (1.014 g, 3.6 mmol) were added in anhydrous dichloromethane (20 mL) and the mixture was stirred at room temperature overnight. The mixture was extracted with dichloromethane (100 mL×4) and the organic phase was dried with anhydrous sodium sulfate and evaporated under reduced pressure. 1.2 g benzyl-3-(2-hydroxy-3-(methoxycarbonyl)phenylcarbamoyl)piperidine-1-carboxylate was obtained. Yield: 97%. LC-MS (ESI) m/z: 413 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:21][C:22]2[CH:26]=[CH:25][O:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>CN1C(=O)CCC1>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[CH:3]=[C:4]([NH:21][C:22]3[CH:26]=[CH:25][O:24][N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:29]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Nc3ccon3)cc(Cl)nn12
Solvent: CN1CCCC1=O
Product: N[C@H]1CC[C@H](Nc2cc(Nc3ccon3)c3ncc(C(=O)Nc4ccncc4F)n3n2)CC1
Temperature: 110 °C

Procedure:
A mixture of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(isoxazol-3-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (20 mg, 0.054 mmol) and trans-cyclohexane-1,4-diamine (61.1 mg, 0.535 mmol) in NMP (0.4 mL) was heated at 110° C. overnight, then cooled to room temperature. The resulting mixture was purified by reversed-phase preparative HPLC. The desired fractions were concentrated and dried to give 18.7 mg of 6-((trans-4-aminocyclohexyl)amino)-N-(3-fluoro-4-pyridinyl)-8-(3-isoxazolylamino)imidazo[1,2-b]pyridazine-3-carboxamide as a beige solid. HPLC Rt=2.292 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm), [M+1]=452.
Reaction SMILES: [CH3:1][N:2]=[C:3]([NH2:18])[NH:4][CH:5]([C:13]1[N:14]=[CH:15][S:16][CH:17]=1)[S:6][CH2:7][CH2:8][C:9](=[NH:12])OC.[N:19]#[C:20][NH2:21]>C(O)C>[C:20]([NH:21][C:9](=[NH:12])[CH2:8][CH2:7][S:6][CH:5]([NH:4][C:3]([NH2:18])=[N:2][CH3:1])[C:13]1[N:14]=[CH:15][S:16][CH:17]=1)#[N:19]
Reactant: N#CN
Reactant: CN=C(N)NC(SCCC(=N)OC)c1cscn1
Solvent: CCO
Product: CN=C(N)NC(SCCC(=N)NC#N)c1cscn1
Yield: 31.4 %

Procedure:
In 30 ml of ethanol was dissolved 6.4 g of methyl 3-(2-methylguanidinothiazol-4-ylmethylthio)propionimidate and after adding thereto 0.9 g of cyanamide and stirring the mixture for 2 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue obtained was purified by column chromatography using a mixture of chloroform and methanol as the developing solvent and recrystallized from ethanol to provide 2.0 g of N-cyano-3-(2-methylguanidinothiazol-4-ylmethylthio)propionamidine showing a melting point of 144°-145° C.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].Cl>>[CH3:29][S:30]([C:33]1[CH:34]=[C:35]([NH:39][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:28])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:36]=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CS(=O)(=O)c1cccc(N)c1
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Agent: Cl
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(C)(=O)=O)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-methanesulfonyl-phenylamine [commercially available as hydrochloride] according to general procedure II. Yellow solid. MS (ISP) 555.3 [(M+H)+]; mp 211° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C.[CH2:31]1[O:41][C:40]2[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][C:33]=2[O:32]1>CN(C=O)C.C(Cl)Cl>[O:41]1[C:40]2[CH:39]=[CH:38][C:35]([CH2:36][N:19]3[CH2:20][CH2:21][CH:16]([NH:15][C:6]4[C:5]5[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=4)[CH2:17][CH2:18]3)=[CH:34][C:33]=2[O:32][CH2:31]1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: COc1ccc2c(c1)c(NC1CCNCC1)cc(=O)n2C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(NC1CCN(Cc3ccc4c(c3)OCO4)CC1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 6-methoxy-1-methyl-4-(piperidin-4-ylamino)-1H-quinolin-2-one (300 mg, 0.8 mmol) and diisopropylethlyamine (705 uL, 4 mmol) in DMF (5 mL) was added a solution of 3,4 methylenedioxybenzyl chloride in methylene chloride (231 uL, 0.9 mmol, 50% by weight in CH2Cl2). After stirring at room temperature for 2 hours, the reaction mixture was diluted up with methylene chloride, washed with brine and dried with MgSO4. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the title compound (66.4 mg, 20%): 1H NMR (300 MHz, CDCl3) δ 1.58-1.72 (2H, m), 2.10-2.23 (4H, m), 2.88-2.98 (2H, m), 3.40-3.50 (1H, m), 3.48 (3H, s), 3.64 (3H, s), 4.58 (1H, bd, J=7.5), 5.75 (1H, s), 5.95 (2H, s), 6.77 (2H, s), 6.89 (1H, s), 7.25 (1H, d; J=1.89 Hz), 7.26 (1H, s), 7.40 (1H, dd, j=1.79, 8.75 Hz).
Reaction SMILES: F[C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[NH3:21]>CO>[CH3:11][S:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[C:2]=1[NH2:21])(=[O:10])=[O:9]
Reactant: CCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Reactant: N
Solvent: CO
Product: CCCN1CCC(c2cccc(S(C)(=O)=O)c2N)CC1
Temperature: 160 °C

Procedure:
4-[2-fluoro-3-(methylsulfonyl)phenyl]-1-propylpiperidine (0.45 g, 1.52 mmol) was dissolved in a solution of ammonia in methanol (7 M, 15 ml). The mixture was heated to 160° C. in a sealed tube under microwave radiation for 20 h. The solvent was evaporated and the crude product was purified on a preparative HPLC-system. Yield: 0.125 g (30%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 232-233° C. MS m/z (relative intensity, 70 eV) 296 (M+, 22), 267 (bp), 224 (31), 130 (23) 117 (20).