Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].O>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: N#Cc1cnc2ccsc2c1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccsc2c1Oc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), potassium carbonate (194.9 mg, 1.41 mmol) and 2,4-dichlorophenol (218.3 mg, 1.34 mmol) in 3 mL of N,N-dimethylformamide is stirred at 110° C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture is treated with water and stirred at ambient temperature for 10 minutes. The crude solid is collected by filtration washing with water, dried in vacuo, then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 244 mg of 7-[(2,4-dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 158-160° C.; 1H NMR (DMSO-d6) δ 7.63 (dd, J=6, 2 Hz, 1H), 7.68 (d, J=4 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.80 (d, J=2 Hz, 1H), 8.33 (d, J=4 Hz, 1H), 9.03 (s, 1H); MS 320.9, 322.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:11])[CH3:10].C1C=C[NH+]=CC=1.[O-:18][Cr](Cl)(=O)=O.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)Cc1ccccc1Cl
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)C(=O)c1ccccc1Cl
Reaction time: 21.5 h

Procedure:
To a solution of 2-chlorophenylacetone (7.14 g, 42 mmol) in CH2Cl2 (184 mL), PCC (27 g, 127 mmol, 3 eq) and pyridine (10 mL, 127 mmol, 3 eq) in three portions were added over five hours at reflux under vigorous stirring. After the addition was complete, the mixture was further refluxed under vigorous stirring for 21.5 h. The mixture was filtered through a pad of silica gel, washed the pad with CH2Cl2, and concentrated under reduced pressure to provide a dark red syrup. The residue was purified by column chromatography on a 120 g of Redi-Sep™ column using 0-15% gradient of EtOAc in hexane over 40 min as eluent to provide 1-(2-chlorophenyl)propane-1,2-dione as yellow liquid. 1H NMR (choroform-d) δ ppm 7.66 (1H, dd, J=7.6, 1.8 Hz), 7.48-7.54 (1H, m), 7.37-7.46 (2H, m), 2.58 (3H, s). Mass Spectrum (ESI) m/e=182.9 (M+1).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:46]1([CH2:52][O:53][NH2:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:24][O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:12][C@H:11]1[N:34]1[C:35]2[N:36]=[C:37]([Cl:44])[N:38]=[C:39]([NH:54][O:53][CH2:52][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]=2[N:41]=[CH:42]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC[C@H]1O[C@@H](n2cnc3c(NOCc4ccccc4)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Yield: 43.4 %

Procedure:
(This example was also prepared by general method A). 9-(2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol), O-(phenylmethyl)hydroxylamine hydrochloride (0.77 g, 4.8 mmol) and diisopropylethylamine (1.03 g, 8.0 mmol) were dissolved in dioxan (50 ml). The reaction mixture was heated at reflux for 20 h, filtered and evaporated in vacuo. The crude product was coevaporated with dichloromethane and crystallised from a mixture of dichioromethane and methanol to provide the title compound (1.0 g, 43%), as white crystals, mp 115°-119° C., 1H NMR (CDCl3)γ 3.52-3.70 (2H, m, H-5'a and H-5'b) 3.95 (1H, d, H-4'), 4.15 (1H, dd, H-3'), 4.52 (1H, dd, H-2'), 5.00 (2H, s, CH2), 5.88 (1H, d, H-1'), 8.52 (1H, s, H-8).
Reaction SMILES: [Br:1][C@@H:2]([CH3:6])[C:3](O)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.ClCCl>O1CCCC1>[Br:1][C@@H:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)=[O:4]
Reactant: Cc1cccc(N)c1
Reactant: C[C@H](Br)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)[C@H](C)Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-(−)-2-bromopropionic acid (0.25 mL, 2.77 mmol), m-toluidine (0.30 mL, 2.77 mmol) and 1-hydroxybenzotriazole hydrate (560 mg, 4.16 mmol) in tetrahydrofuran (25 mL) was added a 1M solution of 1,3-dicyclohexylcarbodiimide in dichloromethane (5.54 mL, 5.54 mmol). The mixture was stirred at about 0° C. for about 2 hours, then it was warmed to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent to provide the desired product. MS (DCI-NH3): m/z 259, 261 (M+NH4)+.
Reaction SMILES: C(=[O:3])C.[CH3:4][OH:5].[N:6]1C=CC=[CH:8][CH:7]=1>C1COCC1>[NH2:6][C@H:7]([C:4]([OH:3])=[O:5])[CH3:8].[NH2:6][C@@H:7]([C:4]([OH:3])=[O:5])[CH3:8]
Reactant: CC=O
Reactant: c1ccncc1
Reactant: CO
Solvent: C1CCOC1
Product: C[C@@H](N)C(=O)O
Product: C[C@H](N)C(=O)O
Temperature: 250 °C

Procedure:
0.10 mol of acetaldehyde and 0.20 mol of L-menthoxyacetamide are heated together at 100° C. with stirring, and the product solid is heated in a sublimator at 250° C. and 1 mm Hg until formation of the enamide L-(menthoxyacetylamino)ethene is complete. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), methanol (20 μL, 0.5 mmol), Co2 (CO)8 (0.05 mmol), pyridine (0.25 mmol,) and L-(menthoxyacetylamino)ethene (0.5 mmol.) The reactor is sealed, pressurized to 1000 psig with CO, and the reaction mixture is stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a mixture of N-(L-menthoxyacetyl)-D-alanine methyl ester and N-(L-menthoxyacetyl)-L-alanine methyl ester. Separation of these products is effected by silica gel chromatography with ether-toluene eluent, and the diastereomers are treated separately with 2N HCl solution at 100° C. for 3 hours to give pure L-alanine and D-alanine.
Reaction SMILES: [Cl-:1].O[CH2:3][CH2:4][NH+:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1.Cl.N1C=CC=CC=1.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl.O>[Cl-:22].[Cl:1][CH2:3][CH2:4][NH+:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH2:7][CH2:6]1
Reactant: O=S1(=O)CC[NH+](CCO)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=S1(=O)CC[NH+](CCCl)CC1
Temperature: 25 °C

Procedure:
4-(2-Hydroxyethyl)thiomorpholin-4-ium 1,1-dioxide chloride, the HCl salt of 41-1, (6.0 g, 27.82 mmol) was treated with pyridine (2.43 g, 30.60 mmol) and then warmed with a solution of thionyl chloride (4.96 g, 41.72 mmol) in chloroform (20 mL) to 60° C. After 1.5 hours the reaction was cooled to 25° C. and water was added. The chloroform was drawn off and the aqueous layer was condensed under reduced pressure to a clear syrup which crystallized upon standing. The crystals were filtered off, washed with 95% ethanol, methanol and then dried to afford 41-2. 1H-NMR (CD3OD): 4.01(t, 2H); 3.90(m, 4H); 3.71(t, 2H); 3.59(t, 4H).
Reaction SMILES: [C:1]1([CH:7]2[C:12](=O)[CH:11]=[CH:10][C:9]([CH2:14][CH2:15][CH2:16][C:17](O)=O)=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:20].[NH2:21][NH2:22]>C(O)(C)C>[C:1]1([CH:7]2[C:8]([C:9]3[CH:10]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:22][NH:21][C:11](=[O:20])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O
Reactant: NN
Reactant: O=C(O)CCCC1=CC(c2ccccc2)C(=O)C=C1
Solvent: CC(C)O
Product: O=C1CC(c2ccccc2)C(c2ccccc2)=NN1
Temperature: 0 °C

Procedure:
To a mixture of 3.0 gms of the product from Step A in 25 ml of isopropyl alcohol was added 1.0 ml of hydrazine hydrate and the mixture was refluxed under nitrogen overnight. The reaction was then cooled to 0° C. and filtered and the solids were washed with water and then cold isopropyl alcohol. This afforded 2.32 g of a white solid, mp 221°-223° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21]C)=[C:16]([O:19]C)[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1>O>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1OC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cnc2cc(O)c(O)cc2c1Nc1cccc(Br)c1
Temperature: 207 °C

Procedure:
5.11 g of of 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile and 30.74 g of pyridine hydrochloride were intimately mixed and then heated under nitrogen at 207° C. for an hour. On cooling the reaction was treated with about 100 ml of water and the solid was filtered. This solid was digested with methyl cellusolve and washed with ether to give 3.00 g of 4-[(3-bromophenyl)amino]-6,7-dihydroxy-3-quinolinecarbonitrile: mass spectrum (electrospray, m/e): M+H 356, 358.
Reaction SMILES: [NH2:1][CH:2]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)[C:3]([N:5]([CH2:14][C:15]1[C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)[CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[O:4].[CH2:36]([NH:43][C:44](=[O:54])[NH:45][C@H:46]([CH2:51][CH:52]=[CH2:53])[CH2:47][C:48](O)=[O:49])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[S:23]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:14][N:5]([CH2:6][CH:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:3]([CH:2]([NH:1][C:48](=[O:49])[CH2:47][CH:46]([NH:45][C:44]([NH:43][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:54])[CH2:51][CH:52]=[CH2:53])[CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[CH:29][CH:30]=3)=[O:4])[C:20]=2[N:21]=[CH:22]1
Reactant: C=CC[C@H](CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc2scnc12)C(=O)C(N)Cc1ccc(OC(C)(C)C)cc1)OCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(CC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2scnc12)CC(OCC)OCC)NC(=O)NCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of 2-Amino-N-benzothiazol-4-ylmethyl-3-(4-tert-butoxy-phenyl)-N-(2,2-diethoxy-ethyl)-propionamide in CH2Cl2 (50 mL) was added a solution of (3R)-3-(3-Benzyl-ureido)-hex-5-enoic acid (1.6 g, 6.1 mmol), EDCI (1.17 g, 1.2 eq), HOBt (0.93 g, 1.2 eq), DIEA (2.13 mL, 12.2 mL) in CH2Cl2 (100 mL) stirred for 40 min. The reaction mixture was stirred at room temperature for 14 h, and then diluted with EtOAc, washed with water and brine. The organic layer was dried with Na2SO4 and concentrated in vacuo. The crude compound was used next step without further purification. MS ESI 744 (M+H), 766 (M+Na)
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][CH:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][S:6]1(=[O:21])=[O:20])=[N+]=[N-].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][CH:8]2[CH2:7][S:6](=[O:21])(=[O:20])[CH:5]([CH2:4][NH2:1])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: COc1ccc(CSC2CC(CN=[N+]=[N-])S(=O)(=O)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CSC2CC(CN)S(=O)(=O)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A 0° C. solution, under argon, of 1.4 g of product from Example 179 in 14 ml of dry methylene chloride is treated with 1.19 ml of triethylamine. Hydrogen sulfide gas is slowly bubbled through the cold solution for 20 minutes (the excess gas is trapped in a flask containing an aqueous solution of 5.25% sodium hypochlorite). The mixture is stirred at 0° C. for 2 hours, the flask flushed for 20 minutes with argon and the reaction is concentrated in vacuo. The residue is purified by chromatography (silica gel: 10-100% ethyl acetate/hexane, 5% methyl alcohol/ethyl acetate) to give 0.757 g of the desired product (mixture of isomers).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N-:11]=[N+:12]=[N-:13].[Na+].Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[NH3:1].[N:5]1[NH:11][N:12]=[N:13][C:4]=1[C:3]1[C:2]([NH2:1])=[N:9][C:8]([NH2:10])=[CH:7][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(N)nc1N
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: N
Product: Nc1ccc(-c2nn[nH]n2)c(N)n1
Temperature: 160 °C
Reaction time: 11 h
Yield: 81.8 %

Procedure:
2,6-Diamino-nicotinonitrile (0.50 g) described in Manufacturing Example 7-2, sodium azide (1.2 g), triethylamine hydrochloride (5.1 g), and NMP (45 mL) were stirred for 11 hours at 160° C. The reaction solution was directly purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol:concentrated aqueous ammonia=6:2:1). The organic layer thus obtained was concentrated and purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol=4:1, then ethyl acetate:methanol:concentrated aqueous ammonia=6:2:1) to obtain the titled compound (270 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:13][NH:14][CH:15]([C:31](=[O:37])[NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:13][NH:14][C@@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)[C:31]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:37]
Reactant: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](N)CN[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 850 mg (1.6 mmol) (1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester in 6 mL dichloromethane was treated with 2 mL 2,2,2-triflouroacetic acid and the resulting solution stirred 1 hour at 25° C. The mixture was concentrated at reduced pressure to a viscous amber oil to which was dissolved in 8 mL diethyl ether, and treated with 3 mL of diethyl ether which had been saturated with hydrogen chloride gas. The solvent was removed under reduced pressure, and the pale yellow oil thus obtained ((S,S)-2-(2-amino-4-methyl-pentylamino)-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide) was used directly in the next reaction.
Reaction SMILES: N1[C:9]2[C:4](=CC=[CH:7][CH:8]=2)C=N1.CO[C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:13].C1(CBr)CC1.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1>>[S:30]1[CH:31]=[CH:32][N:33]=[C:29]1[NH:28][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[N:16]([CH2:4][CH:9]2[CH2:8][CH2:7]2)[CH:15]=1)=[O:13]
Reactant: c1ccc2[nH]ncc2c1
Reactant: Nc1nccs1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: BrCC1CC1
Product: O=C(Nc1nccs1)c1cn(CC2CC2)c2ncccc12

Procedure:
Azaindole starting material=1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester; R5X=cyclopropyl-methylbromide; NH2A=2-aminothiazole
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:21][CH3:22])([C:15]2[S:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:23].[CH2:25]([Mg]Br)[CH3:26].[CH2:29]1COC[CH2:30]1>>[CH2:13]([C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:2])([CH2:25][CH3:26])[CH2:29][CH3:30])=[C:7]([CH3:23])[CH:8]=1)([C:15]1[S:16][CH:17]=[C:18]([CH3:20])[CH:19]=1)[CH2:21][CH3:22])[CH3:14]
Reactant: CC[Mg]Br
Reactant: CCC(CC)(c1ccc(OCC(=O)OC)c(C)c1)c1cc(C)cs1
Reactant: C1CCOC1
Product: CCC(O)(CC)COc1ccc(C(CC)(CC)c2cc(C)cs2)cc1C
Temperature: 0 °C
Yield: 87 %

Procedure:
{4-[1-Ethyl-1-(4-methyl-thiophen-2-yl)-propyl]-2-methyl-phenoxy}acetic acid methyl ester (5.52 g, 15.95 mmol) is dissolved in THF (50 mL). The solution is cooled to 0° C., and treated with Ethyl magnesiumbromide (3.0 M, 13.3 mL) in a dropwise fashion. The reaction is stirred at 0° C. for 10 m, and refluxed for 3 h. It is cooled to 0° C., quenched with sat. NH4Cl (50 mL), then 1.0 M HCl (30 mL) is added. It is extracted with EtOAc (2×100 mL), dried and concentrated. The crude product is purified by chromatography to give the titled compound (5.22 g, 13.96 mmol, 87%). 1H NMR (CD3Cl3), δ 0.71 (t, J=7.4 Hz, 6H), 0.95 (t, J=7.1 Hz, 6H), 1.62-1.73 (m, 4H), 2.04-2.14 (m, 4H), 2.21 (s, 6H), 3.81 (s, 2H), 6.59-6.61 (m, 1H), 6.69-6.74 (m, 2H), 7.02-7.08 (m, 2H). LC/MS (m/z): calcd for C23H35O2S (M+H)+:375.6; found: 375.3.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:7]([NH:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[CH3:31]I.O>CN(C)C=O>[CH3:1][C:2]([CH3:28])([CH:7]([N:17]([CH3:31])[S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)C(Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(C)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)C(Cc1ccc(OC)cc1)N(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Yield: 96 %

Procedure:
A solution of 405 g of methyl 2,2-dimethyl-4-(p-methoxyphenyl)-3-(p-toluenesulphonamido)butyrate in 1800 ml of dry dimethylformamide is added to a mechanically stirred suspension of 52.8 g of sodium hydride in 320 ml of the same solvent. After the reaction mixture has been heated at 80° C. for 1 hour it is cooled when 93 ml of methyl iodide is added. After an additional period of heating (under reflux) the mixture, after being cooled, is poured into plenty of water. A white crystallisate separates. After filtration and drying it melts at 132°-134° C. Yield 96%.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2)[CH3:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:51]1[C:52]([C:60]2[CH:61]=[C:62]([NH2:66])[CH:63]=[CH:64][CH:65]=2)=[CH:53][N:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=12>CN(C=O)C>[N:51]1[C:52]([C:60]2[CH:61]=[C:62]([NH:66][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][CH2:10][CH3:11])=[O:26])[CH:63]=[CH:64][CH:65]=2)=[CH:53][N:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=12
Reactant: CCOc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 41.9 %

Procedure:
DIEA (40.9 μL, 0.23 mmol) was added to 8-ethoxy-3-carboxy-coumarin (50.0 mg, 0.21 mmol) and HATU (89.29 mg, 0.23 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (44.7 mg, 0.21 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 37.4 mg of product in 42% yield: LCMS (ESI) m/z 426 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].C([Sn](CCCC)(CCCC)/[CH:35]=[CH:36]\[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)CCC>CS(C)=O.O1CCOCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9]([NH:12][C:13]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]3[C:16]([C:17]4[CH:29]=[CH:28][O:27][C:18]=4[CH2:19][O:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[C:2](/[CH:35]=[CH:36]\[CH2:37][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:7]=1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OCc1occc1-2
Reactant: CCCC[Sn](/C=C\CN1CCCC1)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCc1occc1-2
Temperature: 90 °C
Yield: 38.9 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-4H-furo[2,3-c]chromene-6-carboxylate (Intermediate 7, 0.300 g) and 1-((Z)-3-tributylstannanyl-allyl)-pyrrolidine (Intermediate 54, 0.390 g) in DMSO (2 mL) and dioxane (8 mL) was de-gassed and purged with nitrogen before tris-(dibenzylideneacetone)dipalladium (0) (0.076 g) and tri-tert-butylphosphonium tetrafluoroborate (0.048 g) were added and the mixture was heated at 90° C. for 3 hours. After cooling, the mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water, dried (MgSO4), and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of 2M ammonia in methanol and DCM, with a gradient of 0-10%. The resultant product was triturated with ether to give methyl 7-{4-fluoro-2-[(Z)-3-(pyrrolidin-1-yl)prop-1-enyl]benzenesulfonyl-amino}-4H-furo[2,3-c]chromene-6-carboxylate (0.124 g), as a pale orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=O)=[CH:5][CH:4]=1.[CH2:12]([SH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:21]>C1(C)C=CC=CC=1>[CH2:12]([S:19][C:7](=[S:21])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: SCc1ccccc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Product: COc1ccc(C(=S)SCc2ccccc2)cc1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 4-methoxybenzoic acid (1.52 g), benzyl mercaptan (1.24 g) and phosphorus pentasulfide (4.44 g) in toluene (40 ml) was refluxed for 12 h. A dark red color was developed immediately after heating. After the reaction was complete (as monitored by GC-MS), it was cooled to room temperature and purified by a column chromatography packed with neutral alumina, eluting with benzene. Removal of the solvent by distillation gave the single compound, benzyl-4-methoxydithiobenzoate (1.89 g, 69%). It was further characterized by 1H and 13C-NMR.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][C:7]1[CH2:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=1>C(OCC)(=O)C>[BrH:1].[CH3:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][C:7]1[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=1
Reactant: Cc1ccccc1CC1=NNC(=O)CC1
Reactant: BrBr
Solvent: CCOC(C)=O
Product: Br
Product: Cc1ccccc1Cc1ccc(=O)[nH]n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of bromine (5.3 ml.) in ethyl acetate (5.3 ml.) was added over 15 minutes to a refluxing solution of 6-(2-methylbenzyl)-2,3,4,5-tetrahydropyridaz-3-one (prepared as described above; 19.2 g.) in ethyl acetate (150 ml.). Heating under reflux was continued for a further 15 minutes. The reaction mixture was then cooled to 0° C. and filtered. Solid 2,3-dihydro-6-(2-methylbenzyl)pyridaz-3-one hydrobromide thus obtained was washed with n-hexane, dried in vacuo, added to an excess of aqueous sodium bicarbonate solution, stirred with a magnetic stirrer for one hour and filtered. The residue was washed with water and dried in air at 60° C. to give 2,3-dihydro-6-(2-methylbenzyl)pyridaz-3-one (13.9 g.) in the form of a fawn coloured powder, m.p. 139°-141° C.