Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.[I:14]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[I:14]
Reactant: II
Reactant: Fc1cccc(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
(Roe, A. M.; Burton, R A.: Willey, G. L., Baines, M. W., Rasmussen, A. C. J. Med. Chem. 1968, 11, 814-819. Tamborski, C., Soloski, E. J. Org. Chem. 1966, 31, 746-749. Grunewald, G. L.; Arrington, H. S.; Bartlett, W. J.; Reitz, T. J.; Sall, D. J. J. Med. Chem. 1986, 29, 1972-1982.) 1,3-Difluorobenzene (57.05 g, 0.5 M) in THF (75 mL) was added to a −78° C. stirred solution of n-butyllithium (n-BuLi) (200 mL, 2.5 M/hexanes, 0.5 M) and THF (500 mL) under N2. By controlling the addition rate the internal temperature was maintained below −70° C. The total addition time was ˜½ hour. The resulting slurry was stirred an additional ½ hour, then the dispersion was treated with a solution of iodine (126.9 g, 0.5 M) in THF (300 mL) at a rate that maintained an internal temperature below −70° C. After complete addition the mixture was allowed to warm to room temperature, and was treated with H2O (100 mL) and 10% aqueous Na2S2O3 solution (100 mL) and stirred. The layers were separated and the aqueous layer extracted with hexanes (2×250 mL). The combined organic layer was washed with 10% aqueous Na2S2O3 solution (100 mL), H2O (100 mL), saturated aqueous NaCl solution (100 mL), dried (Na2SO4) filtered and concentrated to give a yellow oil (106.5 g). Distillation at ˜1-5 mm at ˜80° C. provided a light yellow oil (89.5 g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.87 (m, 2H) GCMS m/e 240 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]([O:22]CC=C)=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]([C:11]1[CH:12]=[C:13]([C:20]([OH:22])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCOC(=O)c1cc(C(=O)OCc2ccccc2)c2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: O=C(OCc1ccccc1)c1cc(C(=O)O)n2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of indolizine-1,3-dicarboxylic acid 3-allyl ester 1-benzyl ester (300 mg, 0.895 mmol) in THF (6 mL) were added Pd(PPh3)4 (34.5 mg, 0.09 mmol) and morpholine (260 mg, 8.95 mmol). The reaction mixture was stirred at RT under nitrogen atmosphere for 30 min. The reaction mixture was diluted in EtOAC, extracted twice with HCl 1N and the combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to give the desired compound which was used without further purification in the next step TLC, Rf (CH2Cl2/MeOH 9:1)=0.4: MS (LC/MS): 294.0 [M−H]−; tR (HPLC conditions a): 3.62 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Reactant: Clc1ccc(-n2cnc3ccc(Br)cc32)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, off-white solid (44 mg, 35%), MS (ISP) m/z=389.4 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-phenyl)-1H-benzo[d]imidazole (intermediate H) (100 mg, 325 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (80.3 mg, 390 μmol).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:11][C:10](=O)[C:9]([C:13]#[N:14])=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:10]1[C:9]([C:13]#[N:14])=[CH:8][C:7]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(-c2ccncc2)c(-c2ccco2)[nH]c1=O
Product: N#Cc1cc(-c2ccncc2)c(-c2ccco2)nc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
A suspension of 6-(2-furyl)-2-oxo-5-(4-pyridyl)-1,2-dihydro-3-pyridinecarbonitrile (21.0 g, 79.8 mmol) in phosphorus oxychloride (90 g) was stirred in a nitrogen atmosphere at 110° C. After 4 hours, additional phosphorus oxychloride (50 g) was added thereto, followed by heating under stirring for further 5 hours. After cooling as it was, the reaction solution was concentrated. After ice was added to the residue, it was neutralized with saturated sodium bicarbonate. After extracting with ethyl acetate (2 1)-tetrahydrofuran (1 1), the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. After adding diethyl ether to the residue, the resulting solid was collected by filtration and washed with diethyl ether, to give the title compound (13.6 g, 61%) as a dark yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([OH:14])=[O:13])[C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:15][C:9]1([CH3:16])[C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:11][C@H:10]1[C:12]([O:14][CH2:23][C:20]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)=[O:13]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To a stirred solution of (1R,3S)-3-(tert-butoxycarbonyl)-2,2-dimethylcyclobutanecarboxylic acid (step 2, 0.200 g) in DMF (5 ml) Cs2CO3 (0.371 g) was added at about 0° C. under nitrogen atmosphere. After 30 minutes, BnBr (0.11 ml) was added by drop wise to the reaction mixture and stirred for about 2 hours at room temperature. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give crude product which upon column chromatography afforded the title compound (150 mg, 53.9% Yield). 1H NMR (300 MHz, CDCl3): δ 7.37-7.34 (5H, m), 5.12 (2H, d, J=3.9 Hz), 2.80 (1H, t, J=8.1 Hz), 2.768-2.52 (2H, m), 2.0 (1H, m), 1.44 (9H, m), 1.32 (3H, s), 0.953 (3H, s); Mass: [M+Na]+ 341.2 (100%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40]3[S:41][C:42]4[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=4[N:44]=3)=[CH:35][CH:34]=2)O1.NC1N=CN=C2N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=C(C3C=CC(NC4OC5C=CC=CC=5N=4)=C(F)C=3)C=12>>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]4[S:41][C:42]5[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=5[N:44]=4)=[CH:35][CH:34]=3)[C:10]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)cc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6o5)c(F)c4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6ccccc6s5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-1,3-benzothiazol-2-amine was prepared from cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.227 mmol) and N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine (0.100 g, 0.283 mmol) in a manner similar to that used for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.035 g, 28%): 1H NMR (DMSO-d6, 400 MHz) δ 10.71 (s, 1H), 8.23 (s, 1H), 7.98 (d, 2H), 7.84 (d, 1H), 7.65 (d, 3H), 7.35 (t, 1H), 7.19 (t, 1H), 4.80 (m, 1H), 3.50 (m, 1H), 2.67-2.09 (m, 15H), 1.71-1.57 (m, 4H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.47 min., 100%; m/z 540 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1.[Cl:23][C:24](Cl)([Cl:28])[CH2:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:23][C:24]([Cl:28])=[CH:25][CH2:26][O:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[C:4]([Cl:9])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cc(O)cc2Cl)CC1
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)CC1
Yield: 24.1 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step C, by the reaction of 2.8 grams (0.008 mole) of tert-butyl 4-(2,6-dichloro-4-hydroxyphenyl)piperazinecarboxylate, 2.2 grams (0.012 mole) of 1,1,1,3-tetrachloropropane and 1.7 grams (0.012 mole) of potassium carbonate in 75 mL of DMF. The crude reaction product was purified with column chromatography on silica gel using 50% hexane in methylene chloride and finally 100% methylene chloride as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.88 gram of the subject compound. The NMR spectrum was consistent with the proposed structure. The reaction was repeated to obtain additional material for the next reactive step.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[CH:9][C:8]=1[OH:15]>>[Cl:4][C:9]1[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=[C:7]([Cl:6])[C:8]=1[OH:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Product: Oc1c(Cl)cc(Cl)c(Cl)c1Cl

Procedure:
As the concentration of sulfuryl chloride increases, over-chlorination occurs, i.e., the 2,4,5-trichlorophenol becomes chlorinated to form more 2,3,4,6-tetrachlorophenol. The 2,3,4,6-tetrachlorophenol present becomes unacceptably high when the ratio of sulfuryl chloride to dichlorophenol significantly exceeds 1.3 to 1.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[CH3:1][C:2]1[C:11]([CH3:12])=[C:10]([N+:15]([O-:17])=[O:16])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2
Reactant: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c2c1C
Reaction time: 2 h

Procedure:
To a solution of 5,6-dimethyl-1,4dihydro-quinoxaline-2,3-dione (28.5 g, 150 mmol) in concentrated H2SO4 (50 mL) was added KNO3 (15.15 g, 150 mmol) portionwise keeping temperature below 5° C. Reaction mixture was stirred for 2 hours and poured over ice. Yellow precipitate was filtered, washed, and air dried.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCCCC(=O)Cl
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)Nc1ccc(Cl)cc1C(=O)OC
Yield: 61 %

Procedure:
To a solution of methyl 2-amino-5-chlorobenzoate (15 g) and triethylamine (12 ml) in methylene chloride (150 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (10 ml). The mixture was stirred at room temperature for further two hours. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and water, followed by drying. The solvent was distilled off to afford a pale yellow crystals (13.4 g, 61%), m.p. 48°-49° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([OH:6])=[O:5].O[CH:16]([CH2:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH3:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)C>[CH3:17][CH:16]([O:5][C:4](=[O:6])[C:3]1[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1])[CH2:18][CH2:19][C:20](=[O:26])[CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCCCC(=O)CCC(C)O
Reactant: COc1cc(O)c(C(=O)O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: C=CCCCC(=O)CCC(C)OC(=O)c1c(O)cc(OC)cc1OC
Yield: 65.2 %

Procedure:
A solution of 2-hydroxy-4,6-dimethoxy-benzoic acid (0.36 g, 0.18 mmol), 2-hydroxy-dec-9-en-5-one (0.024 g, 0.14 mmol), PPh3 (0.042 g, 0.16 mmol), diethyl azodicarboxylate (25 μL, 0.15 mmol) in diethyl ether (1.5 mL) was stirred at room temperature for 7 hours. Concentration under vacuum and chromatography afforded 2-hydroxy-4,6-dimethoxy-benzoic acid 1-methyl-4-oxo-non-8-enyl ester as a light yellow oil (32 mg).
Reaction SMILES: C1(N2C3C(=CC=CC=3)C(CCCN3CCC(C4C=C(NC(=O)C(C)C)C=CC=4)CC3)=C2C2C=CC=CC=2)C=CC=CC=1.[CH3:43][CH:44]([CH3:73])[C:45]([NH:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]2[CH2:59][CH2:58][N:57]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][C:65](=O)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:56][CH2:55]2)[CH:49]=1)=[O:46].Cl.[CH3:75][O:76][C:77]1[CH:82]=[CH:81][C:80]([NH:83]N)=[CH:79][CH:78]=1>>[CH3:75][O:76][C:77]1[CH:82]=[C:81]2[C:80](=[CH:79][CH:78]=1)[NH:83][C:65]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)=[C:64]2[CH2:63][CH2:62][CH2:61][CH2:60][N:57]1[CH2:58][CH2:59][CH:54]([C:50]2[CH:49]=[C:48]([NH:47][C:45](=[O:46])[CH:44]([CH3:43])[CH3:73])[CH:53]=[CH:52][CH:51]=2)[CH2:55][CH2:56]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Reactant: COc1ccc(NN)cc1
Agent: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)n(-c4ccccc4)c4ccccc34)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccccc3)c(CCCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1
Yield: 32.7 %

Procedure:
According to the procedure used for the synthesis of N-(3-{1-[3-(1,2-diphenyl-1H-indol-3-yl)propyl]-4-piperidinyl}phenyl)-2-methylpropanamide, 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide (14.3 mg, 0.0339 mmol) and 1-(4-methoxyphenyl)hydrazine hydrochloride (7.10 mg, 0.0407 mmol) provided N-(3-{1-[4-(5-methoxy-2-phenyl-1H-indol-3-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.8 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, 2H, J=7.8 Hz), 7.61–7.15 (m, 11H), 6.97 (d, 1H, J=7.0 Hz), 3.88 (s, 3H), 3.09 (d, 2H, J=11.3 Hz), 2.99 (t, 2H, J=7.0 Hz), 2.55–2.35 (m, 4H), 2.12–1.70 (m, 6H), 1.68–1.52 (m, 2H), 1.48–1.34 (m, 2H), 1.25 (d, 6H, J=6.7 Hz); ESMS m/e: 524.3 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2)(=[O:25])=[O:24]>C1COCC1>[N:35]1[C:36]2[C:31](=[CH:30][CH:29]=[CH:28][C:27]=2[NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:25])=[O:24])[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
Isobutyryl chloride (42 mg, 0.40 mmol) and DIPEA (100 mg, 0.83 mmol) were added to a solution of 2-amino-N-quinolin-8-yl-benzenesulfonamide (Example Compound 8) (100 mg, 0.33 mmol) in THF (3 ml) at 0° C. The reaction was stirred at room temperature for 1 h. The reaction was quenched water and extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (49:1) as the eluent to give the title compound (43 mg, 36%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[C:21]([C:24]5[CH:25]=[N:26][N:27]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:28]=5)[C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:35][N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:35][N:36]1[CH:40]=[C:39]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[C:21]([C:24]6[CH:25]=[N:26][N:27]([CH:29]7[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]7)[CH:28]=6)[C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:38]=[N:37]1
Reactant: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Oc1c(N)ncc2c(-c3cnn(C4CCNCC4)c3)coc12)c1nnc2ccc(-c3cnn(C)c3)nn12
Temperature: 100 °C

Procedure:
A suspension of 7-[(S)-1-(6-Chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)furo[3,2-c]pyridin-6-ylamine (0.289 mmol, 1 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.507 mmol, 2.7 eq), Pd(PPh3)4 (66.8 mg, 0.0578 mmol, 20 mol %), and K2CO3 (200 mg, 1.45 mmol, 5.0 eq) in a 4:1 ratio of dioxane (4 mL) to H2O (1 mL) was evacuated and charged with nitrogen several times. The reaction sample was then heated in a microwave reactor at 100° C. for 0.5 h. CH2Cl2 and H2O were added and a standard aqueous workup was performed. The crude material was purified by chromatography on an SCX column and HPLC giving the title compound as a diformate salt. 1H NMR (400 MHz, CD3OD): δ=2.15 (d, J=6.8 Hz, 3H), 2.25-2.40 (m, 4H), 3.18-3.28 (ddd, J=12.9, 11.6, 3.8 Hz, 2H), 3.59 (dt, J=13.3, 3.3 Hz, 2H), 3.85 (s, 3H), 4.60 (dddd, J=10.0, 4.9, 4.8 Hz, 1H), 6.34 (q, J=6.6 Hz, 1H), 7.62 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 7.84 (s, 2H), 8.03 (s, 1H), 8.04 (s, 1H), 8.08 (s, 1H), 8.13 (d, J=9.6 Hz, 1H), 8.34 (br s, 4H). MS (ES+): m/z 526.17 (20) [MH+]. HPLC: tR=1.94 min (ZQ3, polar—5 min).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([S:23]([CH3:22])(=[O:25])=[O:24])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
To a solution of 1-(4-bromophenyl)piperazine hydrochloride (5.09 g, 18.3 mmol) and triethylamine (7.67 ml) in dichloromethane (100 ml) was added methanesulfonyl chloride (2.83 ml, 36.3 mmol) dropwise. The mixture was stirred for 1 hour at room temperature then dichloromethane (100 ml) was added. The organics were washed with water (2×), brine and dried (Na2SO4) and evaporated in vacuo to a yellow solid which crystallised from Ethanol and washed with diethyl ether to give 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (4.74 g, 81% yield) as a white fluffy powder.
Reaction SMILES: [Na+:1].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[K+]>O>[Na+:1].[NH:12]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][S:8]([O-:11])(=[O:10])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)([O-])CCCCCBr
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCCCCNc1ccccc1
Yield: 79.9 %

Procedure:
The mixture is washed with ether and the aqueous layer is concentrated to give white solids. The solids are dissolved in ethanol with heating, and cooled slowly to room temperature to precipitate sodium bromide. The precipitates are filtered off and the filtrate is put in a refrigerator overnight to obtain 5-bromo-t-pentanesulfonic acid sodium salt (12.9 g, 68%) as white crystals. A solution of 5-bromo-1-pentanesulfonic acid sodium salt (12.9 g, 0.05 mol) and aniline (20 g, 0.22 mol) in water (150 mL) is heated under reflux with potassium bicarbonate (6.3 g, 0.075 mol) for 8 hr. After the reaction is completed, the reaction mixture is washed with ether and the aqueous layer is concentrated to give white solids. The solid is recrystallized in methanol to obtain 5-anilino-1-pentanesulfonic acid sodium salt (10.6 g, 80%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27](Cl)=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].O1CCCCC1[O:40][C@@H:41]([CH3:44])[CH2:42][OH:43]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:33]=[CH:32][C:15]3[NH:16][C:17]([NH:19][C:20]([C:22]4[N:23]=[C:24]5[CH:29]=[CH:28][C:27]([O:43][CH2:42][C@@H:41]([OH:40])[CH3:44])=[N:26][N:25]5[CH:31]=4)=[O:21])=[N:18][C:14]=3[CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: O=C(Nc1nc2cc(-c3ccc(C(F)(F)F)c(Cl)c3)ccc2[nH]1)c1cn2nc(Cl)ccc2n1
Reactant: C[C@@H](CO)OC1CCCCO1
Product: C[C@H](O)COc1ccc2nc(C(=O)Nc3nc4cc(-c5ccc(C(F)(F)F)c(Cl)c5)ccc4[nH]3)cn2n1

Procedure:
6-((S)-2-Hydroxy-propoxy)-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (38 mg) was prepared from 6-chloro-imidazo[1,2-b]pyridazine-2-carboxylic acid [5-(3-chloro-4-trifluoromethyl-phenyl)-1H-benzoimidazol-2-yl]-amide (80 mg) and (S)-2-(tetrahydro-pyran-2-yloxy)-propan-1-ol (100 μL) as described above in Example 122. LCMS (m/z): 532. 1H NMR (400 MHz, DMSO-d6): δ 12.5 and 11.5 (1H, brs) 8.85 (1H, s) 8.14 (1H, d) 8.02 (1H, brs) 7.85-7.93 (3H, m) 7.55-7.63 (2H, m) 7.07 (1H, d) 5.01 (1H, d) 4.17 (2H, d) 4.02-4.07 (1H, m) 1.19 (3H, d).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:31])[CH2:29][CH3:30]>C(Cl)(Cl)Cl>[CH2:28]([NH:31][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH3:30]
Reactant: CCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 85.6 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroform ate in 40 ml of chloroform is added dropwise to the above mixture at -10° C. during 20 minutes. After stirring for 5 minutes, a solution containing 5.2 g (0.088 mol) of propylamine in 80 ml of chloroform is added dropwise at -15° C. during 30 minutes, then the mixture is stirred for 1 hour below -10° C. Then the mixture is allowed to stand overnight under cooling by ice. For working up, the chloroform mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The chloroform phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 16.8 g (85.6%) of the named product in the form of yellow crystals after recrystallization from ethanol, m.p.: 158°-160° C.