Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=O>>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: COc1cccc(C(=O)/C=C/N(C)C)c1
Agent: Cl
Product: COc1cccc(-c2ccnn2-c2cc(C#N)ccn2)c1
Yield: 98 %

Procedure:
The title compound was prepared in 98% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-methoxyphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.78 (3H, s), 6.53 (1H, s), 6.81-6.85 (2H, m), 6.90-6.93 (1H, m), 7.24-7.28 (1H, m), 7.38 (1H, dd, J=5.6, 1.2 Hz), 7.77 (1H, d, J=2.0 Hz), 7.93 (1H, s), 8.44 (1H, dd, J=5.2, 0.8 Hz).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH:28]([CH2:31][CH2:32][CH3:33])[C:29]#[N:30].O>CN(C=O)C>[C:29]([CH2:28][CH2:31][CH2:32][CH2:33][C:12]([CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=1)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])#[N:30]
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Reactant: CCCC(Br)C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCCCC#N)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
1.88 g (78.23 mmol) of sodium hydride are added in portions to a solution of 20 g (60.18 mmol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate from Example 12A in 140 ml of DMF at 0° C. The reaction solution is then warmed to 40° C. and is stirred at this temperature for 30 min. The reaction solution is then cooled to 0° C. again and, after addition of 10.73 g (66.20 mmol) of bromovaleronitrile in 140 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 9:1→4:1). 15.5 g (37.49 mmol, 62% yield) of a colorless solid are obtained.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10].Br[CH2:15][CH2:16][CH:17]=[CH2:18].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:11]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: C=CCCBr
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 21.4 %

Procedure:
To a solution of sodium hydride (14.8 g, 60% dispersion in mineral oil) in dimethylformamide (DMF, 150 ml) at 0° C. under nitrogen was added a solution of 3,4-dichlorophenylacetonitrile (68.9 g, 1 mol. equivalent) in DMF (300 ml) and the mixture was stirred for 3 hours. A solution of 4-bromobut-1-ene (50 g, 1 mol. eq.) in DMF (100 ml) was then added, and the mixture was stirred at room temperature for one hour, then heated to 60° C. for 5 hours. The reaction mixture was cooled and water (1 liter) was added. The mixture was then extracted with ethyl acetate (2×500 ml). The combined organic extracts were then washed with water (2×1 liter), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was then purified by column chromatography using silica gel, eluting with a solvent gradient of ethyl acetate:hexane (1:19 to 1:6, by volume) to give the title compound (51.5 g).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][O:31]C6CCCCO6)[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl>CO.O1CCOCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][OH:31])[CH2:27][CH2:28]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCOC4CCCCO4)CC3)cc1OCC2
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCO)CC3)cc1OCC2
Reaction time: 0.75 h
Yield: 30.5 %

Procedure:
A solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-piperidin-4-yl}-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (371 mg, 0.73 mmol) in methanol (3.5 mL) was treated with 4N HCl in dioxane (3.5 mL) and the mixture stirred for 45 min before being concentrated in vacuo. The resultant residue was re subjected to the reaction conditions as before and stirred for 1 h at RT before being concentrated in vacuo. The resultant residue was partitioned between DCM/saturated aqueous sodium hydrogen carbonate, the aqueous extracted twice with DCM and the combined organic extracts washed with brine and then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, column preconditioned with 1% TEA in DCM, gradient 0 to 7% methanol in DCM) to give 293 as a yellow foam (94 mg, 30%). LCMS: RT=2.61 min, [M+H]+=423. 1H NMR 400 MHz (DMSO-d ) δ: 8.32 (1 H, d, J=8.28 Hz), 7.89 (2 H, d, J=1.96 Hz), 7.05 (1 H, dd, J=8.31, 1.76 Hz), 6.89 (1 H, d, J=1.71 Hz), 5.88-5.87 (1 H, m), 4.49 (4 H, q, J=5.91 Hz), 3.53 (2 H, t, J=7.21 Hz), 3.03 (2 H, d, J=11.27 Hz), 2.52 (3H, m), 2.16 (2 H, t, J=11.38 Hz), 1.76 (2 H, d, J=12.61 Hz), 1.67 (2 H, d, J=12.75 Hz), 1.47 (6 H, d, J=6.60 Hz)
Reaction SMILES: CC1(C)[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:27][CH2:28][N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:35][CH2:36][CH2:37][CH2:38][C@H:4]2[O:3]1.C(N(CC)CC)C>C(Cl)Cl.Cl>[O:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH2:27][O:26][C:24]2[CH:23]=[CH:22][C:21]3[N:17]([CH2:16][C:14]4[CH:13]=[CH:12][C:10]5[N:11]=[C:7]([NH:6][C@@H:5]6[CH2:35][CH2:36][CH2:37][CH2:38][C@H:4]6[OH:3])[S:8][C:9]=5[CH:15]=4)[CH:18]=[N:19][C:20]=3[CH:25]=2)[CH2:34][CH2:33]1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCN5CCOCC5)ccc43)cc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(OCCN5CCOCC5)ccc43)cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.3 %

Procedure:
To a stirred mixture of (3aR,7aR)-2,2-dimethyl-3-(6-((5-(2-morpholino ethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole (85 mg, 0.15 mmol) from the previous step in DCM (10 mL) at 0° C. was added methanolic HCl (3 drops). The reaction mixture was stirred at 0° C. for 10 min. The mixture was adjusted to pH˜7 by addition of triethylamine and then concentrated under reduced pressure. The residue was purified directly by reverse-phase preparative HPLC to afford (1R,2R)-2-((6-((5-(2-morpholinoethoxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (20 mg, 25%) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.97 (m, 1H), 7.62 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.1 Hz, 1H), 7.17 (d, J=6.9 Hz, 2H), 6.83 (m, 1H), 5.41 (s, 2H), 4.73 (d, J=5.4 Hz, 1H), 4.08 (t, J=11.7 Hz, 2H), 3.57 (t, J=9.1 Hz, 4H), 3.47-3.52 (m, 2H), 2.68 (t, J=11.7 Hz, 2H), 2.46 (t, J=9.3 Hz, 4H), 2.02 (m, 1H), 1.87 (m, 1H), 1.59-1.63 (br s, 2H), 1.16-1.28 (m, 4H). LCMS (ESI) m/z 508 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=1[OH:24])[CH2:12][CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Ni]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH2:13][OH:14])=[C:16]([OH:24])[CH:17]=1
Reactant: O=C(OCc1ccccc1)N(CCO)c1ccc([N+](=O)[O-])cc1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1ccc(N(CCO)C(=O)OCc2ccccc2)c(O)c1
Reaction time: 1 h

Procedure:
0.24 mole (80 g) of 2-[N-benzyloxycarbonyl-N-(β-hydroxyethyl)amino]-5-nitrophenol in 630 ml of ethyl acetate is subjected to a hydrogen pressure of 9×105 pascals (9 bars) in an autoclave in the presence of 15 g of Raney nickel (water content 50%). After one hour at 85° C., the reaction medium is filtered while hot in order to remove the catalyst. On evaporation of the solvent under vacuum, the expected product crystallizes. After draining and drying, the product obtained is recrystallized from 96° strength alcohol It melts at 142° C.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14].FC1C=CC(N[C@H](CC)C(O)=O)=C([N+]([O-])=O)C=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C@H:13]([C:15]([OH:17])=[O:16])[CH3:14])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C[C@H](N)C(=O)O
Agent: CC[C@@H](Nc1ccc(F)cc1[N+](=O)[O-])C(=O)O
Product: C[C@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O

Procedure:
2,4-Difluoronitrobenzene was treated with L-alanine according to the procedure for the preparation of (R)-2-(4-fluoro-2-nitrophenylamino)-butyric acid (see Example 1) to yield N-(5-fluoro-2-nitrophenyl)-L-alanine. MS (ESI) m/z 229 ([M+H]+); MS (ESI) m/z 227 ([M−H]−); Anal. Calcd for C9H9FN2O4: C, 47.37; H, 3.98; N, 12.28. Found: C, 47.61; H, 4.23; N, 12.39.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[N:36]=[C:37]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH3:52])[CH2:47][CH2:46]2)[C:38]2[C:43]([CH:44]=1)=[CH:42][CH:41]=[CH:40][CH:39]=2>C1(C)C(C)=CC=CC=1.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>[CH2:51]([N:48]1[CH2:47][CH2:46][N:45]([C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:44]=[C:35]([C:18]3[CH:17]=[CH:16][C:15]([S:12](=[O:13])(=[O:14])[NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:20][CH:19]=3)[N:36]=2)[CH2:50][CH2:49]1)[CH3:52]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)NCCOCc2ccccc2)cc1
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: CCN1CCN(c2nc(-c3ccc(S(=O)(=O)NCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Yield: 48.8 %

Procedure:
N-(2-Benzyloxyethyl)4-tributylstannylbenzenesulfonamide (0.92 g) and 3-bromo-1-(4-ethylpiperazin-1-yl)isoquinoline (0.42 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.09 g) in xylene in nitrogen atmosphere for 45 min. After cooling, the reaction solution was filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol system). The resulting product was dissolved in ethyl acetate and extracted with 2N hydrochloric acid. The aqueous layer was washed with ethyl acetate, adjusted to pH 10 with a 8N aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. The extract was washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)sulfamoyl]phenyl}isoquinoline (0.34 g) as a pale brown oil.
Reaction SMILES: ClC1N=CC(C2C=CC3N(C=C(NC(=O)C)N=3)N=2)=CC=1NS(C)(=O)=O.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[N:35]=2)[N:32]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CS(C)=O.C([O-])(=O)C.[K+].Br[C:68]1[CH:69]=[C:70]([O:76][CH3:77])[C:71]([O:74][CH3:75])=[N:72][CH:73]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:77][O:76][C:70]1[CH:69]=[C:68]([C:27]2[CH:28]=[CH:29][C:30]3[N:31]([CH:33]=[C:34]([NH:36][C:37](=[O:39])[CH3:38])[N:35]=3)[N:32]=2)[CH:73]=[N:72][C:71]=1[O:74][CH3:75]
Reactant: COc1cc(Br)cnc1OC
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(C)(=O)=O)c3)ccc2n1
Agent: CC(=O)[O-]
Solvent: CS(C)=O
Product: COc1cc(-c2ccc3nc(NC(C)=O)cn3n2)cnc1OC
Reaction time: 0.33 h
Yield: 16.3 %

Procedure:
Following the procedure described for N-(6-(6-chloro-5-(methylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 19), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (0.132 g, 0.627 mmol) was reacted with bis(pinacolato)diboron (0.207 g, 0.815 mmol), DMSO (6.00 mL, 84.5 mmol) and potassium acetate (0.246 g, 2.51 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.050 g, 0.062 mmol, Strem Chemical, Inc., Newburyport, Mass.) for 6 h. This was followed by treatment with 5-bromo-2,3-dimethoxypyridine (0.136 g, 0.624 mmol), aq sodium carbonate (0.312 mL, 0.624 mmol, 2 M) and trans-dichlorobis(triphenylphosphine)palladium(II) (0.0438 g, 0.0624 mmol, Strem). Purification by preparative HPLC (Phenomenex Gemini 5 micron (Phenomenex, Torrance, Calif.), C18, 100×30 mm, 5 to 65% CH3CN(0.1% TFA)/H2O(0.1% TFA) over 20 min then 100% CH3CN(0.1% TFA) for 3 minutes at 20 mL/min) followed by conversion to the free base by loading the purified material onto a 1000 mg SCX (cation exchange resin, Radleys Discovery Technology, Essex, UK) cartridge and elution with MeOH(2M NH3)/CH2Cl2 which, after concentration, afforded the title compound (0.0318 g, 16%) as a yellow solid. MS (ESI, positive ion) m/z: 314 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 3.92 (s, 3H), 3.95 (s, 3H), 7.83 (d, J=9.6 Hz, 1H), 7.87 (d, J=2.0 Hz, 1H), 8.05 (d, J=9.6 Hz, 1H), 8.29 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 10.89 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[CH:22]1([OH:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.O>C(OCC)C>[C:1]([O:38][CH:22]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: OC1CCCCCCC=CCCCCCCC1
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OC1CCCCCCC=CCCCCCCC1
Yield: 36.1 %

Procedure:
1.8 g of dodecanoyl chloride and 2.0 ml of triethylamine are added to a solution of 1.65 g of 8-cyclohexadecen-1-ol in 25 ml of diethyl ether. After heating to reflux for 5 hours, the mixture is poured into 100 ml of H2O, the organic phase is separated off, the aqueous phase is extracted with 25 ml of diethyl ether, and the combined organic phases are evaporated in vacuo. Purification of the residue by chromatography on silica gel using dichloromethane/hexane 1:3 gives 1.05 g of 8-cyclohexadecen-1-yl dodecanoate as a viscous oil.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([N:8]([CH3:28])[C:9]2[C:10]3[CH:17]=[CH:16][N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH:4]([CH2:29][S:30]([OH:33])(=O)=[O:31])[CH2:3]1.C(Cl)[Cl:35].CN(C=O)C.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][CH:2]1[CH:7]([N:8]([CH3:28])[C:9]2[C:10]3[CH:17]=[CH:16][N:15]([S:18]([C:21]4[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=4)(=[O:20])=[O:19])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:6][CH2:5][CH:4]([CH2:29][S:30]([Cl:35])(=[O:33])=[O:31])[CH2:3]1
Reactant: ClCCl
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)O)CC4C)ncnc32)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCC(CS(=O)(=O)Cl)CC4C)ncnc32)cc1
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
A mixture of (3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonic acid (0.400 g, 0.81 mmol), CH2Cl2 (10 mL), and DMF (50 uL) was treated with thionyl chloride and warmed to 40° C. After 1.5 h, the mixture was cooled, treated with toluene (5 mL) and concentrated. The resulting material was triturated with Et2O and dried to afford (3-methyl-4-(methyl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonyl chloride that was used immediately without additional manipulation. MS for C22H27ClN4O4S2 (ESI) (MH)+ m/z=512.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:21][C:22](=O)[CH2:23][CH3:24])[C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[O-]CC.[Na+].O>C(O)C>[CH2:23]([C:22]1[CH2:21][N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=2)[C:11](=[O:20])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)[CH3:24]
Reactant: CCC(=O)CN(C(=O)Cc1cccc(Cl)c1)c1cccc(C(C)C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC1=C(c2cccc(Cl)c2)C(=O)N(c2cccc(C(C)C)c2)C1
Yield: 81.5 %

Procedure:
7.61 g (21.3 mmol) of N-(3-isopropylphenyl)-N-(2-oxobutyl)-3-chlorophenylacetamide synthesized in Example 2 or 3 were dissolved in 35 ml of ethanol, and 0.1 ml of an ethanol solution containing 30% of sodium ethoxide was added at room temperature with stirring. The solution was successively stirred at the same temperature for 2 hours, and the resultant reaction mixture was poured into water, followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure, and the solution was then purified through silica gel column chromatography (an eluent: hexane/ethyl acetate=4/1) to obtain 5.9 g of the desired product in an oily state (yield: 77.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH:16]1[CH2:20][CH2:19][CH2:18][CH:17]1[NH2:21])[CH3:14].Cl>C(O)(C)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:21][CH:17]3[CH2:18][CH2:19][CH2:20][CH:16]3[N:15]([CH2:22][CH3:23])[CH2:13][CH3:14])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CCN(CC)C1CCCC1N
Agent: Cl
Solvent: CC(C)O
Product: CCN(CC)C1CCCC1Nc1ccnc2cc(Cl)ccc12

Procedure:
8.16 g of base from 16 g of 4,7-dichloroquinoline and 12.7 g of 2-(diethylamino)cyclopentylamine (16 hours reaction duration at 140° C.). By addition of isopropanolic hydrochloric acid to a solution of the diamine in isopropanol were precipitated 7.84 g of dihydrochloride; colourless crystals from acetonitrile/ethanol, m.p.: 186°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][C:24](=O)[CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:18]([CH3:35])[CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([NH:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:18]([CH3:35])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(NC(=O)CCOc4ccccc4)cc3C)c2cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3cc(C)c(NCCCOc4ccccc4)cc3C)c2cc1OC
Temperature: 0 °C
Yield: 79.9 %

Procedure:
N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylphenyl}-3-phenoxypropaneamide (200 mg) was dissolved in tetrahydrofuran (10 ml) to prepare a solution. A 1 M solution (1.3 ml) of a borane-tetrahydrofuran complex in tetrahydrofuran was then added to the solution, and the mixture was stirred with heating under reflux for 2 hr. The reaction solution was cooled to 0° C. and was adjusted to pH=1 by the addition of 1 N hydrochloric acid, followed by stirring with heating under reflux for 30 min. The reaction solution was cooled to 0° C., was adjusted to pH=12 by the addition of a 1 N aqueous sodium hydroxide solution, and was extracted with chloroform. After the concentration of the extract, the residue was purified on a column using chloroform/methanol to give the title compound (155 mg, yield 80%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3Br)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:37]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C1COCC1>CN(C=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=3[N:37]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[C:21]#[N:22])=[O:17])[CH2:12][CH2:11]2)=[C:6]([F:27])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3Br)CC2)c(F)c1
Reactant: C1CCCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc(C#N)ccc3N3CCCCCC3)CC2)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 30.1 mg (0.7 mmol) 3-[4-(4-Acetyl-2-fluoro-phenyl)-piperazine-1-carbonyl]-4-bromo-benzonitrile, 30 ul (0.175 mmol) DIPEA and 91 ul (0.91 mmol) of a 1M solution of azepane in DMF was heated to 100° C. for 24 h. After removal of THF 2 ml dioxane, 180 ul of a 1M solution of azepane in DMF and 30 ul (0.175 mmol) DIPEA were added and the mixture was heated to 120° C. for 16 h. After evaporation of all volatiles the residue was taken up in 1 ml MeOH/formic acid 6/1 and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 9.3 mg (30%) of the title compound. MS (m/e): 449.2 (MH+, 100%)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[N:9]=1>CO.O>[Br:7][C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[NH:10][N:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(Br)c3cc(N)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1cnc2[nH]nc(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.2 %

Procedure:
K2CO3 (0.233 g, 1.68 mmol) was added to a solution of 3-bromo-1-tosyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.206 g, 0.56 mmol) in MeOH/H2O (3:1, 8 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The resulting residue was taken up in water (10 mL), and the pH was adjusted to about 7 with acetic acid. The aqueous layer was extracted with ethyl acetate (3×50 mL) The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (1:4) to give 3-bromo-1H-pyrazolo[3,4-b]pyridin-5-amine (0.036 g, 30%) as a solid.