Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([CH2:12][NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH:9]=[CH:8][C:7]=1[Cl:22])=[O:4].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C1COCC1>[Cl:22][C:7]1[CH:8]=[CH:9][C:10]([CH2:12][NH:13][C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[CH2:2][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNC1
Reactant: C[C@@H](NCc1ccc(Cl)c(NC(=O)CCl)c1)c1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](NCc1ccc(Cl)c(NC(=O)CN2CCCC2)c1)c1ccccc1
Temperature: 50 °C
Yield: 65.4 %

Procedure:
To a solution of (R)-2-chloro-N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)acetamide 46 (0.397 g, 1.2 mmol) in THF (6 mL) was added pyrrolidine (3.0 mL, 36 mmol). The reaction mixture was heated to 50° C. for 30 min, cooled to room temperature, partially concentrated under reduced pressure, quenched with saturated NaHCO3, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 1% to 10% MeOH in DCM) gave (R)—N-(2-chloro-5-((1-phenylethylamino)methyl)phenyl)-2-(pyrrolidin-1-yl)acetamide 47 (0.292 g, 67% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.5 Hz, 3H), 1.83-1.91 (m, 4H), 2.68-2.79 (m, 4H), 3.33 (s, 2H), 3.58 (d, J=13.5 Hz, 1H), 3.64 (d, J=13.3 Hz, 1H), 3.81 (q, J=6.7 Hz, 1H), 6.98 (d, J=8.2 Hz, 1H), 7.23-7.37 (m, 7H), 8.38 (s, 1H), 9.93 (s, 1H). Mass spectrum: calculated for C21H26ClN3O 371.2. found 372.2 (M++1).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28]C2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.CN(CC1CCCCC1)C1C=CC(OC)=C(Cl)C=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[Cl:24][C:18]1[CH:17]=[C:16]([N:15]([CH2:25][CH:26]2[CH2:28][CH2:29][CH2:30][CH2:31]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(OC)c(Cl)c2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COc1ccc(N(C)CC2CCCCC2)cc1Cl
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1Cl

Procedure:
The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(3-chloro-4-methoxyphenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(3-chloro-4-methoxy-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([O-:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1.[Na+].C(O)(=O)C>O>[CH3:1][O:2]/[N:3]=[C:4](\[C:11]([NH:13][C@@H:14]1[C:17](=[O:18])[N:16]2[C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH2:21][S:22][C@H:15]12)=[O:12])/[C:5]1[N:9]=[C:8]([NH2:10])[S:7][CH:6]=1
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=CCS[C@H]12)c1csc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 91.8 %

Procedure:
A solution of 5.40 mmol of ceftizoxime sodium salt (equivalent to 2 g of ceftizoxime) in 20 ml of water was acidified with 5.40 ml of 1N acetic acid. The resulting solid was collected and washed with ice water to give 1.90 g of ceftizoxime. A suspension of 1.85 g of ceftizoxime (dried at 80° C./0.1 mm) in 60 ml of methylene chloride was stirred overnight under argon with 2.03 g of N,O-bis(trimethylsilyl) acetamide and 1.73 g of diethyl chlorophosphate, whereupon the solid had dissolved. After a month the reaction mixture was evaporated to dryness and the residue was washed with water. The aqueous washes were extracted with chloroform, back-washing the chloroform extracts with water. Evaporation of the dried (MgSO4) chloroform extracts left 0.049 g of a colorless gum; NMR (CDCl3, 80 MHz) δ 1.37 (t, CH3) δ 1.41 (t, CH3), 4.17 (OCH2, NOCH3); IR (KBr) 1032 (P=O), 1787 (β-lactam).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)(C)C)(C)(C)C.[Li]C(CC)C.CN([CH:25]=[O:26])C.Cl>C1COCC1.C1CCCCC1>[Cl:16][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[C:13]([Cl:15])[C:12]=1[CH:25]=[O:26]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl-(3,5-dichlorophenoxy)-dimethylsilane (2.7 g, 9.8 mmol) in THF (20 mL) at −78° C., under a N2 atmosphere, was added dropwise sec-BuLi (7.2 mL of a 1.4 M solution in cyclohexane, 10.1 mmol). After 30 min, anhydrous DMF (1.2 mL, 15.2 mmol) was added slowly to the solution. After the addition, the solution was stirred at −78° C. for 1.5 h then 20 mL of 1N HCl was added and the suspension was warmed to ambient temperature. The aqueous layer was extracted with EtOAc and the organic layer was washed with water, brine, dried with MgSO4 and filtered. The solvent was removed under reduced pressure to give 2,6-dichloro-4-hydroxybenzaldehyde as a pale yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][C@H:63]([C:68](O)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][C@H:63]([C:68]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:69])[CH2:64][CH:65]([CH3:67])[CH3:66]
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.6 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (200 mg, 0.52 mmol), DCC (129 mg, 0.62 mmol) and DMAP (6 mg, 0.052 mmol) in ethyl acetate (10 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-leucine (183 mg, 0.52 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (210 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 120 mg (47%) of the title compound as an off white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:24]=[CH:23][C:8]([CH2:9][NH:10][C:11]2[C:15]([C:16]#[N:17])=[C:14]([N:18]=[CH:19][N:20](C)C)[NH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][CH:33]=1)N>CO>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[C:15]3[C:14](=[N:18][CH:19]=[N:20][C:16]=3[NH:17][C:32]3[CH:31]=[CH:29][CH:28]=[C:27]([Cl:26])[CH:33]=3)[NH:13][N:12]=2)=[CH:23][CH:24]=1)(=[O:3])[CH3:2]
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)Nc1ccc(CNc2n[nH]c(N=CN(C)C)c2C#N)cc1
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C

Procedure:
A mixture of 0.34 g (1.04 mmol) of 3-(4-acetylamino-benzylamino)-4-cyano-5-(dimethylamino-methyleneamino)-pyrazole, 0.189 g (1.15 mmol) of 3-chloro-aniline hydrochloride and 4 ml of methanol is heated under reflux for 20 hours. Cooling to approx. 20° C., filtering and washing the filter residue with diethyl ether yields the title compound; m.p. >260° C.; TLC-Rf =0.34 (toluene/isopropanol/conc. ammonia [70:29:1]).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Cl)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.2 mmol) dissolved in DCM (10 ml), cooled to 0° C. and added oxalyl chloride (1.2 ml, 13.8 mmol). Catalytic amount of DMF was added to this mixture and stirred at rt for 30 mins. After 30 mins, DCM removed on rotavapour and co-distilled the residue two times with DCM to obtain 2-fluoro-4-(methylsulfonyl)benzoyl chloride quantitatively. 4-Bromo-2-fluoroaniline (1.4 g, 7.37 mmol) dissolved in DCM and added Pyridine (0.7 g, 8.84 mmol) under nitrogen atmosphere. This mixture stirred at rt for 30 mins and added 2-fluoro-4-(methylsulfonyl)benzoyl chloride (2.08 g, 8.84 mmol). After continuing stifling at rt for 15 mins, reaction mixture diluted with water and extracted with DCM. DCM layer washed with aq. NaHCO3 and DCM removed on rotavapour to obtain the solid. Solid was triturated with Et2O and Petether mixture (4:1) to obtain the titled compound (1 g) as a brown solid.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[CH2:38]1[O:49][C:48]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:44][NH2:45])=[CH:41][C:40]=2[O:39]1.C(N(CC)CC)C>>[O:49]1[C:48]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:44][NH:45][C:3]([C:5]3[N:14]4[C:8]([CH2:9][N:10]([C:19]([C:21]5[CH:26]=[CH:25][C:24]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=6[CH3:33])=[C:23]([CH3:34])[CH:22]=5)=[O:20])[C:11]5[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=5[CH2:13]4)=[CH:7][CH:6]=3)=[O:4])=[CH:41][C:40]=2[O:39][CH2:38]1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc5c(c4)OCO5)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6, 3,4-methylenedioxyphenethylamine hydrochloride and triethylamine (2.2 eq.), m.p. 154-157° C. MS [(+)ESI, m/z]: 582 [M+H]+
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[Cl:23][CH2:24][CH2:25][NH2:26].CN1CCOCC1>CN(C=O)C>[Cl:23][CH2:24][CH2:25][NH:26][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(N(C)c2nc(NCCCl)nc3ccccc23)cc1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.671 g (2.0 mmol), 2-chloro-ethylamine hydrochloride 0.58 g (5.0 mmol) and N-methylmorpholine 1.0 mL in DMF 1.0 mL was stirred under microwave irradiation at 130° C. for 20 minutes. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.44-7.46 (m, 1H), 7.34-7.38 (m, 1H), 7.08-7.11 (m, 2H), 6.85-6.91 (m, 3H), 6.65-6.70 (m, 1H), 3.92-3.94 (m, 2H), 3.82-3.84 (m, 2H), 3.82 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].CN(C)C=O.S(Cl)([Cl:73])=O>ClCCl>[CH2:1]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[C:27]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:23][Cl:73])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(CO)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(CCl)cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 30 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
Under an argon atmosphere, 3,4,5-tris(octadecyloxy)benzyl alcohol (10.0 g, 11.0 mmol) was dissolved in dichloromethane (100 mL), N,N-dimethylformamide (84.0 μL, 1.10 mmol) and thionyl chloride (1.20 ml, 16.4 mmol) were added, and the mixture was stirred at 30° C. for 90 min. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, acetonitrile was added, and the precipitated solid was filtered. The obtained solid was dried under reduced pressure to give the title compound (10.0 g, 98.2%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1.Cl.[CH3:14]COC(C)=O>CO>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:14])=[O:11])=[N:4][N:5]([CH3:9])[C:6](=[O:8])[CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cn1nc(C(=O)O)c(Cl)cc1=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1nn(C)c(=O)cc1Cl
Temperature: 25 °C
Yield: 7 %

Procedure:
A solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (390 mg, 2.07 mmol) and conc. HCl (0.10 mL) in MeOH (6 mL) was refluxed for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude material that was redissolved into EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography (100% hexanes to 10 to 20 to 30 to 50% EtOAc in hexanes) to afford 72 mg (7%) of the desired product.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1)(=O)=O>CN(C)C=O.O>[N:1]([CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 105 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
Sodium azide (350 mg, 5.38 mmol) was added to a solution of methanesulfonic acid, 2-(2-benzotriazol-1-ylmethyl-benzimidazol-1-yl)-ethyl ester (200 mg, 0.54 mmol) in 5 mL of anhydrous N,N-dimethylformamide. The reaction temperature was raised to 105° C. and stirred for 4 hours. The mixture was cooled, diluted with water and extracted with diethyl ether (3×100 mL). The combined ether extracts were dried over magnesium sulfate, filtered, and evaporated under vacuum. This gave the title compound as a white solid (160 mg, 94% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[C:15]([S:17]([NH:20][CH3:21])(=O)=[O:18])[C:14]([Cl:22])=[CH:13][C:12]=2[O:23][CH3:24])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[OH-:25].[K+]>>[Cl:22][C:14]1[C:15]([S:17]([NH:20][CH3:21])=[O:18])=[CH:16][C:11]([C:9]2[N:10]=[C:2]3[C:7](=[N:6][CH:5]=[N:4][C:3]3=[O:25])[N:8]=2)=[C:12]([O:23][CH3:24])[CH:13]=1
Reactant: CNS(=O)(=O)c1cc(-c2nc(Cl)c3[nH]cnc3n2)c(OC)cc1Cl
Reactant: [OH-]
Agent: [K+]
Product: CNS(=O)c1cc(C2=NC3=NC=NC(=O)C3=N2)c(OC)cc1Cl

Procedure:
Prepared analogously to Example 16 from 6-chloro-(4-chloro-2-methoxy-5-methylaminosulfonyl-phenyl)-purine with 20% potassium hydroxide solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:7]=2[CH:13]=1.C([O-])([O-])=O.[K+].[K+].[C:20](#N)[CH3:21]>ICC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:20][CH3:21])[C:7]=2[CH:13]=1
Reactant: CC#N
Reactant: COc1ccc2c(c1)NCCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Product: CCN1CCCCc2ccc(OC)cc21
Reaction time: 18 h

Procedure:
To a solution of 8-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.5 g) in acetonitrile (25 mL), iodoethane (0.45 mL) and K2CO3 (1.2 g) was added, and the reaction heated to reflux. After stirring for 18 hours, the heat was removed, and the reaction was concentrated. The resulting residue was partitioned between water (30 mL) and EtOAc (25 mL), the layers separated, and the organic layer washed with brine, dried (Na2SO4) and concentrated to provide the title compound (0.54 g) as a clear oil: 1H NMR (DMSO-d6) δ 6.93 (d, 1H); 6.39 (d, 1H), 6.33 (dd, 1H), 3.67 (s, 3H), 3.07 (q, 2H), 2.85-2.82 (m, 2H), 2.62-2.58 (m, 2H), 1.66-1.59 (m, 2H), 1.51-1.43 (m, 2H), 1.10 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1(P([Pd-4](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)C=CC=CC=1>[F:15][C:16]1[CH:17]=[C:18]([N:31]2[CH2:35][C@H:34]([CH2:36][N:37]3[CH:41]=[CH:40][N:39]=[N:38]3)[O:33][C:32]2=[O:42])[CH:19]=[CH:20][C:21]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OC[C@H]1CC(c2ccc(Br)cn2)=NO1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)OC1(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@@H](CO)C3)nc2)c(F)c1
Temperature: 75 °C
Yield: 55.5 %

Procedure:
[(5R)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (intermediate 12, 0.139 g, 0.54 mmol), (5R)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 7, 0.2 g, 0.514 mmol), potassium carbonate (0.355 g, 2.57 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.059 g, 0.05 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane (2×10 ml), the solids were further purified by column chromatography, eluted with 5% DMF in dichloromethane to give the title compound as a white solid (0.125 g).
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N(Br)C(=[O:16])C1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]4([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:44][CH2:43]4)=[O:40])[CH:35]=[C:30]3[C:29]=2[CH3:55])=[CH:24][CH:23]=1.C[N+]1([O-])CCOCC1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[O:54][C:31]3=[N:32][CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([CH:51]=[CH:52][CH:53]=4)[C:39]([NH:41][C:42]4([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=5)[CH2:43][CH2:44]4)=[O:40])[CH:35]=[C:30]3[C:29]=2[CH:55]=[O:16])=[CH:26][CH:27]=1
Reactant: Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: C[N+]1([O-])CCOCC1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: O=Cc1c(-c2ccc(F)cc2)oc2ncc(-c3cccc(C(=O)NC4(c5ccccc5)CC4)c3)cc12
Temperature: 76 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
AIBN (6.5 mg, 0.040 mmol) was added to a stirring solution of NBS (26 mg, 0.15 mmol) and 3-(2-(4-fluorophenyl)-3-methylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (61 mg, 0.13 mmol) in CCl4 (20 ml). The mixture was heated to 76° C. and allowed to stir for 2 hours. The reaction was concentrated and diluted with DMSO (1 mL) and treated with NMO (18.5 mg, 0.158 mmol) and subjected to MW irradiation (150° C.) for 10 min. The mixture was diluted with EtOAc and washed with 10% NaHSO4 2× followed by H2O and Brine. The organic phase was dried over Na2SO4, filtered and concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product 3-(2-(4-fluorophenyl)-3-formylfuro[2,3-b]pyridin-5-yl)-N-(1-phenylcyclopropyl)benzamide (34 mg, 0.071 mmol, 54% yield) consistent by LCMS. LC-MS retention time: 1.64 min; m/z (MH+): 477. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.CI.[O-][CH2:29]C.[Na+]>>[CH3:25][C:2]1([CH3:1])[C:7]2[S:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][CH3:29])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCS1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Product: CCCCCC(C)C(C)c1cc(OC)c2c(c1)OC(C)(C)C1=C2CCS1

Procedure:
By reacting 1,2-dihydro-4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran with methyl iodide in the presence of sodium ethoxide, there is obtained 1,2-dihydro-4,4-dimethyl-9-methoxy-7-(3-methyl-2-octyl)-4H-thieno[2,3-c][1]benzopyran.