Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[OH:16][C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:20]2[CH2:19][CH2:18][C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([OH:16])[CH2:22][CH2:21]2)=[O:15])=[CH:6][CH:7]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-hydroxy-4-phenylpiperidine (10.6 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (3.9 mg). HRMS calcd for C22H22N2O3: 362.1630, found 362.1623.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[N+](C1C=CC([O:21][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=3[F:37])[CH2:26][CH2:25]2)=O)=CC=1)([O-])=O>C1COCC1>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:9][CH2:8][C@@H:4]2[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]2)=[O:21])[CH2:25][CH2:26]1
Reactant: CN1CCO[C@@H](CO)C1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@@H](COC(=O)N2CCN(c3ccc(F)cc3F)CC2)C1
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
(R)-(4-Methylmorpholin-2-yl)-methanol (Intermediate 11; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-(2,4-Difluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (Intermediate 12; 330 mg, 0.91 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) and the solvents were removed in vacuo to give [(2R)-4-methylmorpholin-2-yl]methyl 4-(2,4-difluorophenyl)-piperazine-1-carboxylate (87 mg, 32%) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C([Li])CCC.CN(C)[CH:22]=[O:23]>O>[Cl:1][C:2]1[C:3]([O:9][CH2:10][C:11]([F:12])([F:13])[F:14])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: Fc1ccc(OCC(F)(F)F)c(Cl)c1
Agent: [Li]CCCC
Solvent: O
Product: O=Cc1c(F)ccc(OCC(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.1 %

Procedure:
To 2-chloro-4-fluoro-1-(2,2,2-trifluoro-ethoxy)-benzene (124, 2.10 g, 9.19 mmol), under an atmosphere of nitrogen at −78° C., n-butyllithium (2.50 M in hexane, 3.86 mL) was added slowly. After 60 minutes, N,N-dimethylformamide (0.782 mL, 0.0101 mol) was added to the reaction. After 30 minutes, the reaction was allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound (125, 450 mg, 19.0%).
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15]N)=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4].Cl.O1CCOCC1.N(OCCC(C)C)=O.[N-]=[N+]=[N-].N[C@H:46]([C:54]([NH:56][C@H:57]([C:60]([NH:62][C@H:63]([C:79]([NH:81][C@H:82]([C:88]([OH:90])=[O:89])[CH2:83][CH2:84][C:85](=[O:87])[OH:86])=[O:80])[CH2:64][CH2:65][CH2:66][CH2:67][NH:68][S:69]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)(=[O:71])=[O:70])=[O:61])[CH2:58][OH:59])=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:53])[NH2:52]>CN(C)C=O.C(N(CC)CC)C>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:5]([NH:7][C@H:8]([C:13]([NH:15][C@H:46]([C:54]([NH:56][C@H:57]([C:60]([NH:62][C@H:63]([C:79]([NH:81][C@H:82]([C:88]([OH:90])=[O:89])[CH2:83][CH2:84][C:85](=[O:86])[OH:87])=[O:80])[CH2:64][CH2:65][CH2:66][CH2:67][NH:68][S:69]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)(=[O:71])=[O:70])=[O:61])[CH2:58][OH:59])=[O:55])[CH2:47][CH2:48][CH2:49][NH:50][C:51](=[NH:52])[NH2:53])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6])[CH2:3][OH:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)NN
Reactant: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CCCNC(=N)N)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: CC(C)CCON=O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)OCc2ccccc2)C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
1.03 Grams of Z-Ser-Leu-NHNH2 was dissolved in 15 ml of dimethylformamide, then 1.41 ml of 6N-hydrochloric acid/dioxane was further added thereto, and the mixture was cooled to -15° C., then 0.38 ml of isoamyl nitrite was added under a stirring condition. After the reaction mixture shows a negative reaction in hydrazide test, then a cold solution of 0.40 ml of dimethylformamide with 1.18 ml of triethylamine was added drop by drop in small amounts to neutralize the reaction mixture. This reaction mixture containing the azide was added to 10 ml of a cold dimethylformamide solution containing H-Arg-Ser-Lys(Tos)-Glu-OH obtained in the above-mentioned step 5(a) and 0.66 ml of triethylamine, then whole mixture was stirred at -10° to -15° C. for 2 hours, and at 4° C. for 20 hours. Dimethylformamide was removed by distillation under a reduced pressure and the residue thus obtained was extracted with n-butanol saturated with water and the butanol layer was wahsed 5 times with water being saturated with n-butanol and the solvent was removed by distillation. The residue was solidified by adding ethyl ether, and reprecipitated from methanol-ethyl acetate to obtain 1.92 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1.[CH2:15]([C@@H:17]1[O:19][CH2:18]1)[Cl:16]>>[Cl:16][CH2:15][C@@H:17]([OH:19])[CH2:18][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:3]=1
Reactant: CCC(CC)COc1cccc(Br)c1
Reactant: ClC[C@H]1CO1
Product: CCC(CC)COc1cccc(C[C@H](O)CCl)c1

Procedure:
Metallation of 1-bromo-3-(2-ethylbutoxy)benzene followed by addition to (R)-(−)-epichlorohydrin gave (S)-1-chloro-3-(3-(2-ethylbutoxy)phenyl)propan-2-ol. Yield (1.57 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J=7.8 Hz, 1H), 6.78-6.73 (m, 3H), 5.13 (d, J=5.2 Hz, 1H), 3.88-3.83 (m, 1H), 3.80 (d, J=6.0 Hz, 2H), 3.52 (dd, J=10.8, 4.6 Hz, 1H), 3.43 (dd, J=11.0, 5.8 Hz, 1H), 2.74 (dd, J=13.8, 5.0 Hz, 1H), 2.62 (dd, J=13.6, 7.6 Hz, 1H), 1.61-1.55 (m, 1H), 1.47-1.31 (m, 4H), 0.86 (t, J=7.2 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N+:14]([O-:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N+:14]([O-:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1c[n+]([O-])nc2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1c[n+]([O-])nc2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 100 °C
Reaction time: 3 h
Yield: 151.5 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one-2-oxide (116 mg) and aminoguanidine hydrochloride (49 mg) were added ethanol (3 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 100° C. (bath temperature) for 3 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnolin-2-oxide hydrochloride (Compound 160) (116 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14].[OH-].[Na+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][N:12]=[C:13]([O:15][CH2:16][CH3:17])[CH3:14])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCOC(C)=NO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)=NOc1ccc([N+](=O)[O-])cc1
Temperature: 17 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
4-Chloronitrobenzene, 136.2 g, and 111.4 g ethyl N-hydroxyacetimidate are dissolved in 216 ml DMF. The temperature is adjusted to 30° C. and 41.6 g solid NaOH is added in 8 portions keeping the temperature at 30-35° C. After one hour the temperature is adjusted to 40-45° C. and the mixture stirred for 1.5 hours. Cooling is applied and 520 ml water is fed at such a rate as to keep the temperature at ca 40° C. The slurry formed is cooled to 17° C. and filtered. The filter cake is washed with 175 ml ethanol/water 90/10 (V/V) followed by 175 ml water. Wet product, 214.5 g, corresponding to 192 g dry ethyl N-(4-nitrophenoxy)acetimidate is isolated. Yield 98.5%.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[N:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[N:20]=2)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>O1CCCC1>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[N:20]=[C:21]([CH3:26])[CH:22]=[C:23]([CH3:25])[N:24]=3)[CH:13]=[N:12]2)[C:3]([OH:27])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2nc(C)cc(C)n2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C)nc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.3 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (206 mg, 0.55 mmol) in tetrahydrofuran (4 mL) was treated with a 4N aqueous sodium hydroxide solution (0.17 mL) and was stirred at 25° C. for 4 h. The reaction was partitioned between water (3 mL) and ether. The aqueous layer was back extracted with ether. The aqueous layer was then acidified to pH 3-4 with a 1N aqueous hydrochloric acid solution. The resulting precipitate was filtered, rinsed with water (1 mL), and dried in vacuo to afford 3-cyclopentyl-2-[4-(4,6-dimethyl-pyrimidin-2-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (40 mg, 20%); LC-MS: tR=3.71 min, 359 [M+H]+. HPLC: tR=7.02 min, 96.21% at 214 nm, 98.34% at 254 nm. 1H NMR (300 MHz, DMSO-d6): δ13.03 (broad, 1H), 8.12 (d, 1H, J=2.7 Hz), 7.19 (s, 1H), 6.85 (d, 1H, J=2.4 Hz), 5.36 (dd, 1H, J=10.5 Hz, J=4.2 Hz), 2.41 (s, 6H), 2.24-2.14 (m, 1H), 2.05-1.97 (m, 1H), 1.71-1.44 (m, 7H), 1.17-1.04 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[O:8][C:6]1[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([CH2:25][N:22]3[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]3)=[CH:32][CH:31]=2)[N:7]=1
Reactant: Cc1cnc(Cl)nc1Oc1ccc(F)c(Cl)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Oc1ccc(F)c(Cl)c1
Yield: 59 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-4-(3-chloro-4-fluorophenoxy)-5-methylpyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 59% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ H 8.10 (s, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.23 (d, 2H), 7.09 (d, 2H, J=8.2 Hz), 7.04 (dd, 1H, J=9.6, 2.4 Hz), 6.94 (m, 1H), 3.42 (s, 2H), 2.46 (bs, 8H) 2.27 (s, 3H), 2.18 (s, 3H); MS (ESI): 442.3 [M+H]+, 221.7 [M+2H]2+.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:12]Cl>>[OH:4][CH2:3][CH2:2][N:1]([CH2:12][C:11]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:9]([Cl:8])[CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: ClCc1ccc(Cl)c(Cl)c1
Product: OCCN(CCO)Cc1ccc(Cl)c(Cl)c1

Procedure:
2-[(2-Hydroxy-ethyl)-(3,4-dichloro-benzyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (4.84 g, 46 mmol) and 3,4-dichlorobenzyl chloride (9.0 g, 46 mmol). Yield 13.8 g (99%); colorless oil; MS: 264.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CBr)c1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of 122 g (1.0 mol) of 1-methoxy-3-methylbenzene in 900 ml of CCl4, 178 g (1.0 mol) of NBS and 1.0 g of (PhCO2)2 were added at room temperature. This mixture was refluxed for 3 h, cooled to room temperature, and the formed succinimide was filtered off. Succinimide was additionally washed by 2×150 ml of CCl4. The combined filtrate was evaporated to dryness, and the residue was distilled in vacuum, b.p. 112-125° C./8 mm Hg. This procedure gave 152.5 g of 1-(bromomethyl)-3-methoxybenzene contaminated with ca. 25% of the isomeric product, i.e. 1-bromo-4-methoxy-2-methylbenzene.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[CH:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cnc(CN2CCN(c3c(Br)cnc(N)c3[N+](=O)[O-])CC2)c1
Reactant: COc1ccc(C=O)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cn(C)cn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-4-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.035 g, 0.088 mmol, 1 eq), EtOH (2 mL) and DMF (0.3 mL), p-anisaldehyde (0.013 g, 0.097 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.26 mL, 0.26 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained as a solid after trituration with diethyl ether (0.011 g, 26%); 1H-NMR (500 Mz, DMSO-d6): δ 2.59-2.68 (m, 4H, piperazine N(CH2)2), 3.43 (s, 2H, NCH2), 3.60-3.66 (m, 7H, piperazine N(CH2)2 and imidazole Me), 3.84 (s, 3H, OMe), 7.00 (d, J=1.0 Hz, 1H, imidazole 5-H), 7.10 (d, J=9.0 Hz, 2H, ArH, C6H4), 7.47 (d, J=1.0 Hz, 1H, imidazole 2-H), 8.13 (d, J=9.0 Hz, 2H, ArH, C6H4), 8.19 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.34 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=2.87 min—482/484 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS: Found: 482.1300, calculated for C22H25BrN7O (M+H)+: 482.1304.
Reaction SMILES: CO.[Br:3][C:4]1[CH:5]=[C:6]([C:10]([NH:12][CH2:13][CH2:14]CO)=[O:11])[NH:7][C:8]=1[Br:9].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>C1COCC1>[Br:9][C:8]1[NH:7][C:6]([C:10]2[O:11][CH2:14][CH2:13][N:12]=2)=[CH:5][C:4]=1[Br:3]
Reactant: O=C(NCCCO)c1cc(Br)c(Br)[nH]1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Brc1cc(C2=NCCO2)[nH]c1Br
Temperature: 80 °C
Yield: 66.3 %

Procedure:
Method A. A solution of 10 (0.25 g, 0.77 mmol) in 2 mL of methanesulfonic acid was heated at 60° C. for 3 d. The reaction mixture was diluted with ether (100 mL) and washed with sat. NaHCO3 (20 mL×3) and sat. NaCl (20 mL). The organic layer was dried (MgSO4) and evaporated under reduced pressure. The resulting residue was purified by flash chromatography (EtOAc/hexanes 1:1) to give 14 (0.14 g, 59%) as a colorless solid: 1H NMR (CDCl3) d 2.00 (p, 2H, J=5.7), 3.52 (t, 2H, J=5.7), 4.32 (t, 2H, J=5.7), 6.58 (s, 1H), 10.10 (br, 1H); 13C NMR (CD3COCD3) d 22.2 (e), 41.3 (e), 66.6 (e), 99.1 (e), 109.4 (e), 115.0 (o), 127.7 (e), 153.8 (e); UV (CH3OH) 1max 329, 275 nm; MS m/z (relative intensity) 311 (M++5, 50), 309 (M++3, 100), 307 (M++1, 50); Anal. Calcd for C8H8N2OBr2: C, 31.20; H, 2.62; N, 9.10; Found: C, 31.17; H, 2.51; N, 9.29. Method B. To a stirred mixture of 10 (0.25 g, 0.77 mmol) and p-toluenesulfonyl chloride (0.16 g, 0.77 mmol) in 10 mL of THF was added triethylamine (0.6 mL, 4.27 mmol) at room temperature. The mixture was heated at 80° C. overnight. The solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography (CH2Cl2/MeOH 19:1) to give 14 (0.15 g, 63%) as a colorless solid.
Reaction SMILES: I.CS[C:4]1[NH:5][CH2:6][CH2:7][N:8]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][NH2:18])[CH:13]=[CH:14][C:15]=1[CH3:16]>C1(C)C(C)=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][NH:18][C:4]2[NH:5][CH2:6][CH2:7][N:8]=2)[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: CSC1=NCCN1
Reactant: Cc1ccc(NN)cc1Cl
Agent: I
Solvent: Cc1ccccc1C
Product: Cc1ccc(NNC2=NCCN2)cc1Cl
Temperature: 120 °C

Procedure:
A mixture of 2-methylthio-2-imidazoline hydroiodide (1.83 g, 12 mmol) and 3-chloro-4-methyl-phenylhydrazine (1.87 g, 12 mmol) in xylene (10 ml) was heated to 120° C. overnight. After cooling down to room temperature the precipitate is filtered off and re-crystallised from ethanol, white solid, 0.41 g, MS (ISP): 227.3, 225.3 ([M+H]+.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](F)[N:17]=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.[NH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]1>CS(C)=O>[NH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:5]2[CH:4]=[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:23][CH2:24][C@H:25]4[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[N:17]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:10][CH2:11]1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CN)C1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2cccc(-c3cc(N[C@H]4CC[C@H](N)CC4)ncc3Cl)n2)C1
Temperature: 102.5 °C
Reaction time: 40 h

Procedure:
A mixture of trans-N1-(5′-chloro-6-fluoro-2,4′-bipyridin-2′-yl)cyclohexane-1,4-diamine (Example 1a, step 2) (50 mg, 0.156 mmol), DMSO (0.75 ml), (R)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (167 mg, 0.779 mmol) and TEA (0.033 ml, 0.234 mmol) was stirred at 100-105° C. for 40 hours and the reaction progress was followed by LCMS. The reaction mixture was let cool, added 0.75 ml of DMSO, filtered and purified by prep LC, and lyapholized to yield 36 mg of titled compound as a TFA salt. LCMS (m/z): 515.4 (MH+), retention time=0.64 min.;
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([Br:11])=[CH:9][N:10]=2)[N:7]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1>CS(C)=O>[Br:11][C:8]1[N:6]2[N:7]=[C:2]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2ncc(Br)n2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2ccc3ncc(Br)n3n2)CC1
Temperature: 100 °C

Procedure:
To 6-chloro-3-bromoimidazo[1,2-b]pyridazine (1.00 g, 4.30 mmol, 1.0 equiv) and p-TSA (818 mg, 4.30 mmol, 1.0 equiv) in DMSO (7.00 mL) was added trans-4-aminocyclohexanol (1.49 g, 12.9 mmol, 3.0 equiv). The mixture was heated at 100° C. for 24 h. Purification by column chromatography using 5% methanol in dichloromethane elution gave 1.1 g of the yellow solid, 83%.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[C:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:18][CH:17]=2)[N:3]=1.[H][H]>O1CCOCC1.[Pd]>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[CH:18][CH:17]=2)[N:3]=1
Reactant: [H][H]
Reactant: Cc1nn(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)c(=O)c2ccccc12
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1nn(CCOc2ccc(CC3SC(=O)NC3=O)cc2)c(=O)c2ccccc12
Yield: 79.9 %

Procedure:
##STR41## A solution of 5-[4-[2-[4-methyl-1-oxo-1,2-dihydro-phthalazin-2-yl]ethoxy]phenyl methylene] thiazolidin-2,4-dione (9.0 g, 22.0 mmoles) obtained in example 1, in 1,4-dioxane (500 mL) was reduced with hydrogen in the presence of 10% palladium on charcoal (22.5 g) at 60 psi for 48 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure. The crude compound was recrystallised using CH2Cl2 /pet. ether to afford the title compound (7.2 g, 80%). mp: 170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=[C:5]2O.P(Cl)(Cl)([Cl:19])=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:19][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[N:6]=1
Reactant: Oc1nc(C(F)(F)F)nc2ccc(Cl)cc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nc(Cl)c2cc(Cl)ccc2n1
Yield: 55.2 %

Procedure:
6-Chloro-2-trifluoromethyl-quinazolin-4-ol (1.35 g, 5.43 mmol, 1 eq.), phosphorous oxychloride (4.88 mL, 52.4 mmol, 9.64 eq.) and triethylamine (2.43 mL, 17.4 mmol, 3.21 eq.) were refluxed for 2 hours. Stripped 3× from methylene chloride then dissolved in methylene chloride and rinsed 3× with saturated sodium bicarbonate, 1× with brine. Dried and stripped in vacuo to give an amber oil. Purified over silica gel in 9:1 Hexanes/EtOAc. Obtained 800 mg of off-white solids as product. The product was used immediately in Example 1 Part C.