Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][C:17]([F:16])([F:29])[F:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1OC(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cnccc1I
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-trifluoromethoxyphenylboronic acid after a reaction time of 16 hours at reflux. The crude product was purified by column chromatography eluting with a gradient of n-hexane:EtOAc (80:20 to 70:30). Light yellow sticky liquid (80%). MS (ESI): m/z=355.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:20][CH2:21]OC(C)=O>CN(C=O)C.[Cu]I>[C:20]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17](=[O:19])[CH3:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1)#[CH:21]
Reactant: CCOC(C)=O
Reactant: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C#Cc1cc(Oc2ccc(NC(C)=O)nc2C)ccn1
Temperature: 75 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
A solution of Example A3 (0.35 g, 1.260 mmol) in DMF (5 mL) was sparged with argon, treated with TEA (1 mL) trimethylsilylacetylene (0.531 mL, 3.78 mmol), copper(I) iodide (0.024 g, 0.126 mmol) and trans-dichlorobis(triphenylphosphine)palladium(0) (0.088 g, 0.126 mmol) and heated at 75° C. under argon for 16 h. The mixture was cooled to RT, treated with EtOAc, solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and H2O and the layers of the filtrate separated. The aqueous layer was extracted with EtOAc (1×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. The resulting material was dissolved in MeOH (20 mL), treated with K2CO3 (300 mg) and stirred at RT for 1 h. The mixture was concentrated to dryness, treated with EtOAc, sonicated, the solids removed via filtration through diatomaceous earth, rinsed well with EtOAc and the filtrate concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (102 mg, 30%) as a light red solid. 1H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1 H); 8.40 (d, J=5.8 Hz, 1 H); 8.01 (d, J=8.8 Hz, 1 H); 7.60 (d, J=6.0 Hz, 1 H); 7.04 (d, J=2.5 Hz, 1 H); 6.89 (dd, J=5.8, 2.6 Hz, 1 H); 4.34 (s, 1 H); 2.22 (s, 3 H); 2.07 (s, 3 H); MS (ESI) m/z: 268.1 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:14])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>ClCCl>[OH:14][C:3]1([CH2:2][NH:1][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)N1CCC(O)(CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of ethyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (22.4 mmol, prepared as described above) in dichloromethane (90 mL) was added triethylamine (3.12 mL, 22.4 mmol) and 4-chloro-3-nitroquinoline (3.71 g, 17.8 mmol). The mixture was sonicated and more dichloromethane (10 mL) was added in order to dissolve the 4-chloro-3-nitroquinoline. The solution was allowed to stand at rt for 18 h, then was poured into a reparatory funnel and washed with 1 M NaOH (25 mL), water (2×30 mL), and brine (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated to yield a yellow foam that was crystallized from isopropanol. The solid was isolated by filtration and dried to afford ethyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate as yellow crystals (4.53 g, 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([O:25][CH2:26][CH3:27])[N:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:28]>CC(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([O:25][CH2:26][CH3:27])[N:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH2:28])[C:19]=23)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOc1nc(-c2cccc(OCc3ccccc3)c2)c2c(Cl)nccn12
Solvent: CC(C)O
Product: CCOc1nc(-c2cccc(OCc3ccccc3)c2)c2c(N)nccn12
Temperature: 110 °C

Procedure:
A solution of 1-(3-benzyloxy-phenyl)-8-chloro-3-ethoxy-imidazo[1,5-a]pyrazine (20.0 mg, 0.05 mmol) in i-PrOH (5 mL) was saturated with NH3 at −20° C. and heated in a Parr pressure vessel to 110° C. for 72 h. The reaction was concentrated in vacuo, partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo and purified by chromatography on silica gel [eluting with 2% EtOAc in DCM] to yield the desired product as an off-white solid; 1H NMR (CDCl3, 400 MHz) δ 1.45 (t, J=7.2 Hz, 3H), 4.58 (q, J=7.2 Hz, 2H), 4.91 (brs, 2H), 5.10 (s, 2H), 6.86 (d, J=4.8 Hz, 1H), 6.95-6.99 (m, 1H), 7.04 (d, J=5.2 Hz, 1H), 7.17-7.21 (m, 2H), 7.26-7.43 (m, 7H); MS (ES+): m/z=361.19 (100) [MH+], HPLC: tR=2.36 min (MicromassZQ, polar—5 min).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][S:15]([O:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:7]=1)(=[O:17])=[O:16]
Reactant: OCc1cccc(-n2cccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(-n2cccc2)c1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
170 mg of the resulting alcohol compound was dissolved in 10 ml of methylene chloride, and 120 mg of methanesulfonyl chloride and 150 mg of triethylamine were added. The mixture was stirred for 1 hour under ice cooling. The reaction mixture was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 230 mg (yield 92%) of the captioned compound as a pale yellow oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12].[C:34]1([N:40]=[C:41]=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[NH:17][CH:16]=[N:15][C:14]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:28][CH2:29][N:30]([C:41]([NH:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:42])[CH2:31][CH2:32]2)=[CH:23][C:22]=1[CH3:33])=[O:19])=[O:12]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1cc(N2CCNCC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Solvent: ClCCl
Product: Cc1cc(N2CCN(C(=O)Nc3ccccc3)CC2)ccc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N5-(1H-Benzo[d]imidazol-2-yl)-N4-(2-methyl-4-(piperazin-1-yl)phenyl)-1H-imidazole-4,5-dicarboxamide (1 equivalent) and dichloromethane were stirred for 5 minutes. Phenyl isocyanate (1.5 equiv) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure. The resulting crude product was purified by reverse phase HPLC (aqueous ammonium acetate/acetonitrile to give N5-1H-benzimidazol-2-yl-N4-(2-methyl-4-{4-[(phenylamino)carbonyl]piperazin-1-yl}phenyl)-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 8.86 (s, br, 1H), 8.38 (s, br, 1H), 7.67 (m, 2H), 7.52 (m, 3H), 7.43 (m, 3H), 7.26 (m, 2H), 6.97 (m, 1H), 3.84 (s, br, 4H), 3.41 (s, br, 4H), 2.33 (s, 3H). MS (EI): 564 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].Br.Br[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.BrCC1CCCCO1>>[N:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, (pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 122-123° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.31-7.15 (m, 4H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.24 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.05 (m, 2H), 4.02-3.94 (m, 1H), 2.22-2.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 156.8, 155.4, 153.1, 149.1, 146.3, 142.1, 137.7, 132.2, 129.0, 124.0, 123.7, 123.1, 123.0, 121.9, 116.2, 109.6, 103.6, 80.5, 70.87, 70.85, 58.1, 45.9, 32.2; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH2:14][CH3:15]>>[I:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: Cc1cccc2c(I)n[nH]c12
Reactant: CCCBr
Product: CCCn1nc(I)c2cccc(C)c21
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield from 3-iodo-7-methyl-indazole and 1-bromopropane according to the general procedure for Preparation 4A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.94 (3H, t, J=7.4 Hz), 1.84-1.90 (2H, m), 2.66 (3H, s), 4.50 (2H, t, J=7.4 Hz), 7.01 (1H, t, J=7.1 Hz), 7.11 (1H, d, J=6.9 Hz), 7.28 (1H, d, J=8.0 Hz). [M+H] calc'd for C11H13FN2, 301; found 301.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH2:13][C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.Cl.Cl.[NH2:17][NH2:18].NN.C(O)CO>O>[NH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[C:12]1[NH:18][N:17]=[C:4]([CH2:3][O:2][CH3:1])[CH:13]=1
Reactant: COCC1=Nc2ccccc2C(=O)C1
Reactant: NN
Agent: Cl
Solvent: OCCO
Solvent: O
Product: COCc1cc(-c2ccccc2N)[nH]n1
Yield: 85.5 %

Procedure:
A mixture of 7.5 g (0.04 mol) of 2-methoxymethyl-4-quinolone, 4.2 g (0.04 mol) of hydrazine dihydrochloride, 12.8 ml (0.4 mol) of 95% hydrazine and 30 ml of ethylene glycol is slowly heated to reflux. The resulting solution is refluxed for 5 hours, cooled, diluted with 200 ml of distilled water, and extracted twice with methylene chloride (1×400 ml, 1×200 ml). The combined methylene chloride extracts are washed with 100 ml of distilled water, dried over sodium sulfate, and evaporated to 8.0 g of clear oil. Trituration with 25 ml of hexane gives 6.95 g (86%) of the 5-(2-aminophenyl)-3-methoxymethylpyrazole as a white powder, m.p. 74.0-78.0° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=3)([CH3:13])[CH2:10][C:9]=2[C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:3])[CH3:2].[C:33]([NH:36][NH2:37])([NH2:35])=[NH:34].Cl>C(O)C.N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:6]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:7][C:8]2[O:12][C:11]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[N:37][NH:36][C:33]([NH2:35])=[NH:34])=[CH:18][CH:17]=3)([CH3:13])[CH2:10][C:9]=2[C:24]=1[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(C=O)cc1)O2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc(C=NNC(=N)N)cc1)O2
Yield: 96.7 %

Procedure:
In a mixed solvent of 40 ml of ethanol and 16 ml of pyridine was dissolved 8.54 g of 5-acetoxy-4,6-di-t-butyl-2-(4-formylphenoxymethyl)-2-methyl-2,3-dihydrobenzofuran and 2.38 g of aminoguanidine hydrochloride was added at room temperature. After heating under reflux for 14 hours and then cooling, ethanol and excess pyridine were distilled off using an evaporator and the concentrate was combined with water and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with chloroform containing 5% methanol to give 9.31 g of 1-{4-[(5-acetoxy-4,6-di-t-butyl-2-methyl-2,3-dihydrobenzofuran-2-yl)methoxy]benzylideneamino}guanidine (rotamer mixture) as a pale yellow oil (yield 97%).
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16](Br)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:20]([C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=1)#[CH:21].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.[Pd](Cl)Cl>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:19])[C:11]2[CH:17]=[C:16]([C:21]#[C:20][C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C#Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(C)C(=O)Nc1nc(O)c2cc(Br)cnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
A mixture of 2.0 g of 2-pivaloylamino-4-hydroxy-6-bromopyrido[2,3-d]pyrimidine (prepared according to Example 6), 1.31 g of tert.-butyl 4-ethynylbenzoate, 2.57 ml of triethylamine, 0.11 g of palladium chloride, 0.32 g of triphenylphosphine, and 0.05 g of cuprous iodide in 150 ml of acetonitrile is heated at reflux under nitrogen for 2.5 hours. The reaction mixture is cooled to room temperature and then in an ice bath. The solid is collected and washed with small portions of cold acetonitrile to yield 1.91 g (69%) of 2-pivaloylamino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish powder, which is sufficiently pure for the next reaction. A small sample of this solid, purified further by chromatography on silica gel using a 5% methanol:methylene chloride mixture as the eluent, had the following constants: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.37 (s, 9H), 1.63 (s, 9H), 7.61 (d, 2H, J=8.50 Hz), 8.02 (d, 2H, J=8.50 Hz), 8.42 (brs, 1H), 8.66 (slightly brs, 9.01 (slightly brs, 1H); IR (KBr) 3200, 2980, 1710, 1670, 1600, 1545, 1440, 1375, 1290, 1140, and 770 cm-1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1.[F:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[CH2:34][CH:35]([NH2:37])[CH3:36].C(N(CC)C(C)C)(C)C>C(O)CCC>[F:24][C:25]1[C:30]([F:31])=[CH:29][C:28]([F:32])=[C:27]([F:33])[C:26]=1[CH2:34][CH:35]([NH:37][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:23][C:12]2=[CH:13][C:14]3[C:15](=[O:22])[N:16]([CH3:21])[C:17](=[O:20])[C:18]=3[CH:19]=[C:11]2[N:10]=1)[CH3:36]
Reactant: CN1C(=O)c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2C1=O
Reactant: CC(N)Cc1c(F)c(F)cc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Cc1c(F)c(F)cc(F)c1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C)C3=O
Yield: 75.9 %

Procedure:
2-(4-Chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-methylimidazo[4,5-f]isoindole-5,7(1H,6H)-dione (0.58 g, 1.75 mmol), 1-(2,3,5,6-tetrafluorophenyl)propan-2-amine (0.36 g, 1.75 mmol), n-butanol (30 mL) and N,N-diisopropylethylamine (5 mL) were mixed together in a flask. The reaction mixture was stirred and heated to reflux overnight under argon. Solvents were removed under reduced pressure. The residue solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=9/1 v/v) to give a yellow solid product, 0.66 g, 75.9% yield. MS: 497.8 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 13.44 (s, 1H), 10.90 (d, 1H, J=7.0 Hz), 8.12 (s, 1H), 7.93-7.90 (m, 2H), 7.73-7.71 (m, 1H), 7.40 (d, 1H, J=7.0 Hz), 6.16 (d, 1H, J=7.5 Hz), 4.23 (m, 1H), 3.38 (m, 2H), 3.05 (s, 3H), 1.38 (d, 3H, J=6.0 Hz).
Reaction SMILES: Br[C:2]1[C:3]([S:8][CH2:9][C:10]([O:12]C)=[O:11])=[N:4][CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([C:32]#[N:33])=[CH:24][CH:23]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>O1CCOCC1>[C:32]([C:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22]([C:2]2[C:3]([S:8][CH2:9][C:10]([OH:12])=[O:11])=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:23][CH:24]=1)#[N:33]
Reactant: COC(=O)CSc1ncncc1Br
Reactant: CC1(C)OB(c2ccc(C#N)c3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2cncnc2SCC(=O)O)c2ccccc12
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of methyl 2-(5-bromopyrimidin-4-ylthio)acetate (220 mg, 0.84 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (237 mg, 0.85 mmol) palladium tetrakis triphenylphoshine (46 mg, 0.04 mmol) and aqueous sodium carbonate solution (2M, 1.5 mL, 3 mmol) in dioxane (3 mL) was heated to 100° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and aqueous sodium hydroxide solution added (1M, 30 mL). The mixture was washed with ethyl acetate (2×20 mL), and the aqueous layer acidified to pH 4 resulting in formation of a precipitate which was isolated by filtration and dried under vacuum to yield 2-(5-(4-cyanonaphthalen-1-yl)pyrimidin-4-ylthio)acetic acid (143 mg, 53%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.[N:8]1([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>CN1CCCC1>[F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH2:4][N:11]1[CH2:10][CH2:9][N:8]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:13][CH2:12]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: FC(F)(F)C1CO1
Agent: CN1CCCC1
Product: O=C(OCc1ccccc1)N1CCN(CC(O)C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
0.47 ml of 1,1,1-trifluoro-2,3-epoxypropane is added to a solution of 1 g of benzyl piperazine-1-carboxylate in 100 ml of N-methylpyrrolidine and it is heated at 80° C. for 12 hours. 0.05 ml of 1,1,1-trifluoro-2,3-epoxypropane is added and it is heated at 80° C. for 48 hours, The reaction mixture is extracted with DCM, the organic phase is washed with a 4% solution of LiCl in water, it is dried over MgSO4 and the solvent is evaporated under vacuum. The residue is purified by preparative HPLC and 1.7 g of the expected compound is obtained.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Cl:7][C:8]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([S:20]Cl)[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1>CCOCC>[CH3:6][O:5][C:1]([CH2:2][S:3][S:20][C:13]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[C:11]([O:10][C:9]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:8]=2[Cl:7])[CH:12]=1)=[O:4]
Reactant: COC(=O)CS
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCl
Solvent: CCOCC
Product: COC(=O)CSSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 90 %

Procedure:
5.3 parts by weight of methyl thioglycolate were added dropwise to a solution of 19.2 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzenesulfenyl chloride in 100 parts by volume of absolute ether at room temperature, the reaction mixture was stirred for a further two hours and then evaporated to dryness under reduced pressure, and the oily residue was crystallized using diisopropyl ether. 25 parts by weight (90% yield) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrophenyl methoxycarbonylmethyl disulfide of melting point 66°-68° C. were obtained (compound No. 3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[C:27](=[O:29])=[O:28]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:27]([OH:29])=[O:28])=[CH:3][CH:4]=3)[CH2:9]2)[CH3:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=O
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(Br)cc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(C(=O)O)cc2)C1
Temperature: -78 °C
Yield: 98 %

Procedure:
To a suspension of (2S)-2-(4-bromophenyl)-4-((1R)-1-phenylethyl)morpholine (3.46 g, 10.0 mmol) in tetrahydrofuran (80 ml) was added n-butyllithium (7.7 ml, 12.0 mmol, 1.56 M in hexane) at −78° C. After stirring for 10 minutes, excess of dry ice was added to the mixture and the reaction mixture was maintained at −78° C. for 1.5 hours and then partitioned between diethyl ether and 0.2 N aqueous sodium hydroxide. The aqueous layer was washed with diethyl ether and neutralized with 1N hydrochloric acid. The resulting aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. Filtration of the precipitate gave 4-[(2S)-4-((1R)-1-phenyl-ethyl)-morpholin-2-yl]-benzoic acid (3.05 g, 98%) as white crystals.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([OH:18])=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[C:1]([S:4][CH2:5][C@H:6]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]([C:16]([O:18][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[NH:8][C:7]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)O)NC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC[C@H]1CCCCCC[C@H](C(=O)OCc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylic acid (0.15 g, 0.52 mmol) is dissolved in dimethylformamide (2.5 mL). Benzyl bromide (0.062 mL, 0.52 mmol) and cesium carbonate (0.085 g, 0.26 mmol) are added, and the reaction is stirred at room temperature overnight. The reaction is diluted with water, and the aqueous layer is extracted several times with methylene chloride. The combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (10% ethyl acetate/hexane) to give trans benzyl 3-(acetylthiomethyl)-2-oxo-1-azacyclodecane-10-carboxylate m.p. 117°-118° C.