Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[F:21])=[O:10]
Reactant: NCc1ccccc1F
Reactant: O=C(Cl)c1cccnc1Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1F)c1cccnc1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
In a flask were placed 4 grams (g) (0.01326 mole) 2-(3-trifluoromethylphenoxy)nicotinoyl chloride, dissolved in methylene chloride. There was then added 1.7 g (0.01326 mole) of 2-fluorobenzylamine, very slowly, with vigorous stirring. After about 15 minutes, 1.34 g (0.01326 mole) of triethylamine was added dropwise. The reaction mixture was stirred for a short time, then heated intensely for about 5 minutes and allowed to return to room temperature. After approximately 1/2 hour, 5% aqueous sodium carbonate solution was added with stirring continued. The aqueous and organic phases were separated; the aqueous phase was decanted off and the organic phase washed twice with 5% sodium carbonate solution and twice with water. The organic phase was then dried over sodium sulfate; solvent was stripped off, and an oil-like mixture was recovered, which crystallized in a short time. The solid was then washed with pentane to remove any remaining amine. There was obtained 3.5 g (67% of theoretical yield) which was identified as the desired compounds by infrared, nuclear magnetic resonance, and mass spectroscopic analysis.
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:25]2[N:24]([CH2:28][CH2:29][OH:30])[C:23]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:22][C:21]=2[C:20]=1[C:35]#[N:36].C(N(CC)CC)C>ClCCl>[C:31]([C:23]1[N:24]([CH2:28][CH2:29][OH:30])[C:25]2[C:21]([CH:22]=1)=[C:20]([C:35]#[N:36])[C:19]([NH:18][C:14]([C:11]1([C:9]3[CH:8]=[CH:7][C:5]4[O:6][C:2]([F:17])([F:1])[O:3][C:4]=4[CH:10]=3)[CH2:13][CH2:12]1)=[O:15])=[CH:27][CH:26]=2)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1cc2c(C#N)c(N)ccc2n1CCO
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2c(C#N)c(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (196 mg, 0.75 mmol) was added to a solution of 5-amino-2-tert-butyl-1-(2-hydroxyethyl)-1H -indole-4-carbonitrile (150 mg, 0.58 mmol) and triethylamine (242 μL, 1.74 mmol) in dichloromethane (2 mL). The reaction was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with 1N HCl solution (×2), saturated NaHCO3 solution (×2), brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO and purified by reverse-phase HPLC to yield the product, N-(2-tert-butyl-4-cyano -1-(2-hydroxyethyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 481.2, found 482.5 (M+1)+. Retention time 1.99 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 6.28 (s, 1H), 5.05 (t, J=5.6 Hz, 1H), 4.42 (t, J=6.8 Hz, 2H), 3.70-3.65 (m, 2H), 1.51-1.48 (m, 2H), 1.44 (s, 9H), 1.19-1.16 (m, 2H).
Reaction SMILES: [CH:1]1([CH:4]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:5]([OH:7])=O)[CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:5](=[O:7])[CH:4]([CH:1]2[CH2:2][CH2:3]2)[O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=C(O)C(Oc1cccc2ccccc12)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1)C(Oc1cccc2ccccc12)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.8 %

Procedure:
To a solution of 2-cyclopropyl-2-(1-naphthalenyloxy)acetic acid (120 mg, 0.49 mmol) and 4-chloroaniline (44.0 μL, 0.49 mmol) in anhydrous DCM (10 mL) under N2 cooled at 0° C. was added EDCI-HCl (187.9 mg, 0.98 mmol) portion wise. The resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic extracts were combined, washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using ethyl acetate/n-hexane (a gradient of 5-10%) to furnish 119 (148 mg, 86%) as a white solid. mp 204-206° C.; 1H NMR (CDCl3, 400 MHz) δ 0.65-0.78 (m, 4H0, 1.52 (m, 1H), 4.41 (d, J=6.4 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 7.25 (d, J=6.0 Hz, 3H), 7.43 (d, J=8.4 Hz, 2H), 7.61-7.70 (m, 3H), 7.97 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 2.70, 3.16, 14.42, 82.72, 108.01, 115.68, 121.47, 122.03, 122.96, 127.64, 128.43, 129.28, 129.63, 130.07, 132.96, 135.61, 152.83, 169.27; ESI-HRMS for C21H17ClNO2 (M−H)+calcd. 350.0948. Found 350.0956.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]3)=[C:8]([CH3:22])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][OH:20])[CH2:14][CH2:13]4)=[C:8]([CH3:22])[C:6]=3[N:7]=2)=[CH:38][CH:39]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)CO)CC2)sc2c(N3CCOCC3)nc(-c3ccc(N)nc3)nc12
Yield: 33.8 %

Procedure:
1-(4-((2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone (60 mg) was reacted with 34 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A. The product was purified by reverse phase HPLC to yield 23 mg of 179. MS (Q1) 484.1 (M)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][C@@H:8]2[CH2:10][C@H:5]1[CH2:6][N:7]2[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:3])[CH3:2].[C:18](OC(N1C2CCC1CNC2)=O)(C)(C)C>>[CH:1]([N:4]1[CH:5]2[CH2:10][CH2:18][CH:9]1[CH2:8][N:7]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH2:6]2)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Product: CC(C)N1C2CCC1CN(c1ccc(N)cc1)C2

Procedure:
This compound is prepared according to the same procedure as described for Intermediate 7 using 8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octane (J. Med.Chem., 1998, 41, 674-681).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26]>COCCOC.[I-].[K+]>[CH3:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: COCCOCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(OCCOCCOC)cc1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (2.0 g, 12.04 mmol) in dry DME (50 mL) was added potassium carbonate (3.33 g, 24.07 mmol), potassium iodide (100 mg, 0.602 mmol) and 1-bromo-2-(2-methoxyethoxy)ethane (3.6 mL, 24.07 mmol). The mixture was stirred at reflux for 2 days. After being cooled to rt, the solids were removed by filtration and the solvent by evaporation in vacuo. The remaining crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 5:1) to afford the title compound (2.17 g, 67%): 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 2H), 6.93 (d, 2H), 4.33 (quart, 2H), 4.19 (t, 2H), 3.88 (t, 2H), 3.72 (t, 2H), 3.57 (t, 2H), 3.39 (s, 3H), 1.37 (t, 3H); DCI(NH3)-MS m/z 286 (M+NH4)+; HPLC RT (Method I) 4.14 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.O.Cl>[CH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][C:8]=1[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C1CCC(=O)O1
Reactant: c1ccc2ccccc2c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: O=C(O)CCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
Naphthalene (5.0 gm, 0.039 moles) and succinic anhydride (4.68 gm, 0.0468 moles) were taken up in dichloroethane (50 ml). Aluminium chloride (11.44 g, 0.0858 moles) was added at room temperature and the resulting mixture heated under reflux for 1 hr with stirring. The reaction mixture was cooled to room temperature, diluted with 25 ml of 1:1 mixture of water and Conc. hydrochloric acid. After stirring for 10 min the separated solid was filtered under suction, washed with water and dilute hydrochloric acid. Subsequent column chromatography gave a buff coloured solid. Subsequent chromatography gave 3.7 gm (41%) the title compound, mp 173-174° C.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1O.CCCCCC.Cl.[CH3:19][CH:20]([CH2:22][CH2:23][CH2:24][CH:25]([CH2:27][CH2:28][CH2:29][CH:30]([CH2:32][CH2:33][CH2:34][C:35]([OH:39])([CH:37]=[CH2:38])[CH3:36])[CH3:31])[CH3:26])[CH3:21]>[Cl-].[Zn+2].[Cl-].C(O)CCC>[CH3:9][C:8]1[C:7]([OH:10])=[C:6]([CH3:11])[C:5]2[CH2:38][CH2:37][C@:35]([CH2:34][CH2:33][CH2:32][C@@H:30]([CH2:29][CH2:28][CH2:27][C@@H:25]([CH2:24][CH2:23][CH2:22][CH:20]([CH3:19])[CH3:21])[CH3:26])[CH3:31])([CH3:36])[O:39][C:3]=2[C:2]=1[CH3:1]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCCC(C)CCCC(C)CCCC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: CCCCO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reaction time: 3 h
Yield: 104.7 %

Procedure:
To a mixture consisting of 23.3 g (0.153 mol) of 2,3,5-trimethylhydroquinone, 17.5 g (0.128 mol) of zinc chloride, 47.5 ml of hexane, 2.5 ml of n-butanol and 2.5 g of concentrated hydrochloric acid, 46.1 g (0.153 mol) of isophytol (purity: 98.3%) were added dropwise under stirring at 30°-40° C. over 3 hours. At the same temperature, the reaction mixture was stirred for additional 2 hours. After the reaction mixture was washed with 10 ml of water, the solvents were distilled off. Toluene (100 ml) was added to the residue to dissolve the same. The resulting solution was washed successively with water, alkaline water and a saturated aqueous solution of NaCl, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 69.0 g of the title compound were obtained as a brown oil (yield: 95.9%, GLC purity: 97.2%).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.O>O1CCOCC1.Cl.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>[C:38]([C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:18]([C:20]3[N:21]=[C:22]([CH3:32])[S:23][C:24]=3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:19])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:40])[CH3:39]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(Br)cccc3[nH]2)c(-c2ccc(F)cc2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1cccc2[nH]c(CC3CCCCN3C(=O)c3nc(C)sc3-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 33 %

Procedure:
To a deoxygenated solution of (RS)-1-[2-(4-bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluorophenyl)-2-methylthiazol-4-yl]methanone, E66 (200 mg, 0.39 mmol) in anhydrous 1,4-dioxane (10 ml) was added tributyl(1-ethoxyvinyl)tin (155 mg, 0.43 mmol) and tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The resultant mixture was refluxed under argon for 20 h. Further tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol) was added and refluxing continued for a further 24 h. On cooling, water (15 ml) and 5N hydrochloric acid (10 drops) were added and the mixture stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The combined organics were dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% ethyl acetate-hexane then 2-5% methanol-ethyl acetate) afforded the title compound as a pale orange solid (62 mg, 33%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2].[CH3:28][C:29]1[C:33](B(O)O)=[C:32]([CH3:37])[O:31][N:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:33]2[C:29]([CH3:28])=[N:30][O:31][C:32]=2[CH3:37])=[CH:10][C:9]=1[F:15])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)cc1F
Reactant: Cc1noc(C)c1B(O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(-c2c(C)noc2C)cc1F
Yield: 59 %

Procedure:
By carrying out the operation analogously to example 3, starting from 4-bromo-2-fluorophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation VI, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected compound is obtained in the form of a white solid with a yield of 59%.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1COCC1.Br[CH2:28][C:29]#[N:30]>O>[C:29]([CH2:28][N:12]([C:11]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9][CH:10]=1)[C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])#[N:30]
Reactant: CC(C)(C)OC(=O)Nc1ccnn1-c1ccccc1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC#N)c1ccnn1-c1ccccc1
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl (1-phenyl-1H-pyrazol-5-yl)carbamate (3.80 g), 60% NaH (0.422 g) and THF (60.0 mL) was added bromoacetonitrile (1.93 g) at room temperature, and the mixture was stirred for 30 min. To the reaction mixture was added water, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (4.38 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][N:38]2[CH:42]=[C:41](B(O)O)[CH:40]=[N:39]2)[CH2:32][CH2:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:41]3[CH:40]=[N:39][N:38]([CH2:37][CH2:36][N:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)[CH:42]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1cnn(CCN2CCOCC2)c1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and the solution was purged with argon for 15 min. Then Pd (PPh3)4 (0.1 equiv.) was added and solution was purged again for 10 min. Reaction mixture was heated at 100° C. for 4 h. On completion, the mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.06 g, 25% yield). LCMS: 561.35 (M+1)+; HPLC % 96.87 (@254 nm) (Rt; 4.209; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.15 (s, 1H), 8.06 (t, 1H), 7.81 (s, 1H), 7.22 (s, 1H), 7.06 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 4.21 (t, 2H, J=6 Hz), 3.54 (m, 4H), 2.72 (t, 2H, J=6.8 Hz), 2.61 (s, 3H), 2.40 (m, 4H), 2.20 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.70 (m, 4H), 1.53-1.56 (m, 3H), 1.10-1.23 (m, 4H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]=[C:41]=[O:42])([O-:33])=[O:32]>C1COCC1>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:41]([NH:40][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N+:31]([O-:33])=[O:32])=[O:42])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)Nc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 35.1 mg (0.21 mmol) of 2-nitrophenyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 6 mg (11.2% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1.C(N(CC)CC)C.[S:21](Cl)(=[O:24])(=[O:23])[NH2:22]>CN(C=O)C>[NH2:22][S:21]([N:4]([CH2:5][C:6]1[N:7]2[CH:13]=[N:12][CH:11]=[C:8]2[S:9][CH:10]=1)[CH2:3][CH2:2][OH:1])(=[O:24])=[O:23]
Reactant: OCCNCc1csc2cncn12
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NS(=O)(=O)N(CCO)Cc1csc2cncn12
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A 410 mg potion of 3-[N-(2-hydroxyethyl)amino]methyl imidazo[5,1-b]thiazole was dissolved in 6 ml of DMF, and 1.40 ml of triethylamine and 491 mg of sulfamoyl chloride were added thereto at -30° C., followed by stirring at -30 to -20° C. for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in water, adjusted to pH 7.5 with an aqueous sodium hydrogencarbonate solution, and then purified by Diaion HP-20 Resin and Cephadex LH-20, whereby 59 mg of 3-[N-aminosulfonyl-N-(2-hydroxyethyl)amino]methylimidazo[5,1-b]thiazole was obtained from the first half of the fraction of Cephadex LH-20.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:13](=[O:14])[CH:12]3[CH2:15][CH2:16][CH:17]=[CH:18][CH:11]3[C:10]2=[O:19])=[CH:4][C:3]=1[OH:20].[N+:21]([O-])([OH:23])=[O:22]>>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([N+:21]([O-:23])=[O:22])[C:5]([N:9]2[C:10](=[O:19])[CH:11]3[CH2:18][CH2:17][CH:16]=[CH:15][CH:12]3[C:13]2=[O:14])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C1C2C=CCCC2C(=O)N1c1cc(O)c(Cl)cc1F
Product: O=C1C2C=CCCC2C(=O)N1c1c(F)cc(Cl)c(O)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
2-Chloro-4-fluoro-5-(tetrahydrophthalimido)phenol (5.0 g) was added into nitric acid (50 ml) at 0° C., warmed up to room temperature in 30 minutes. Crushed ice was added and the solution extracted with methylene chloride. The organic phase was washed with water, dried over anhydrous sodium sulfate, and purified by a silica gel column, eluted with metliylene chloride-ethyl acetate (19:1) to give 3.67 g of the desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:36])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]3[CH3:35])[C:15]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][C:16]=3[N:17]=2)=[CH:8][CH:7]=1)[CH3:2].[CH:37]1(NC(NC2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=O)CC1>>[CH:1]1([NH:3][C:4](=[O:36])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH:30]4[CH3:35])[C:15]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:18][C:16]=4[N:17]=3)=[CH:8][CH:7]=2)[CH2:37][CH2:2]1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Product: CC1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCN(C(=O)OC(C)(C)C)C2

Procedure:
Method as described for intermediate 5 using 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:21]I>CN(C)C=O>[CH3:21][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:18])[C:17]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]1=2
Reactant: O=c1c2ccccc2[nH]c2cccc([N+](=O)[O-])c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c2ccccc2c(=O)c2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4.8 g of 1-nitro-9-acridanone are dissolved in 200 ml of dimethylformamide and treated with 0.5 g of sodium hydride. The deep red solution is treated with 2.5 ml of methyl iodide and stirred at room temperature for 4 hours. The yellow precipitate obtained is filtered and washed successively with dimethylformamide, water, ethanol and ether. There is obtained 10-methyl-1-nitro-9-acridanone of melting point 308°-309°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11].O>O1CCCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])=[O:8]
Reactant: CCNCC
Reactant: O=C(Cl)CCCCCBr
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CCCCCBr
Yield: 95.3 %

Procedure:
A solution of 6-bromohexanoyl chloride (100 g, 468 mmol) in 350 ml of tetrahydrofuran was poured into a solution of diethylamine (1.08 moles, 79 g, 112 ml) in 800 ml of rapidly stirring water. The mixture was then extracted with 2×200 ml of CH2C12 and the pooled extracts were washed with 250 ml of brine. Drying over Na2SO4 and concentration under reduced pressure afforded 111.6 g (446 mmol, 100% yield) of product as a pale yellow oil: 1H NMR (Me2SO-d6, 300 MHz) δ 3.5 (t, J=6.7 Hz, 2 H ), 3.2°-3.3 (m, 4 H ), 2.3 (t, J=7.5 Hz, 2 H ), 1.8 (m, 2 H ), 1.3-1.6 (m, 4 H ), 1.1 (t, J=7.1 Hz, 3 H ), 0.99 (t, J=7.0 Hz, 3 H ).