Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH2:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:30][CH3:31]>N.CO>[CH2:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:40])=[O:39])=[CH:34][CH:33]=1)[CH2:30][CH3:31]
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.1 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Propylbenzenesulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound (12.8 mg). MS m/z 371 [M+H]+.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:88]=[CH:87][C:72]([CH2:73][N:74]2[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76][CH2:75]2)=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:70]=[CH:71][C:72]([CH2:73][N:74]4[CH2:75][CH2:76][N:77]([C:80]([O:82][C:83]([CH3:84])([CH3:86])[CH3:85])=[O:81])[CH2:78][CH2:79]4)=[CH:87][CH:88]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cncnc6)CC5)c(Cl)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 44.3 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-3-nitro-4-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (25 mg, 0.071 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.21 mmol, 0.21 mL) and tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate (1.2 eq, 0.085 mmol, 28 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (19 mg, 44%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 2.64 (t, J=4.4 Hz, 4H, piperazine N(CH2)2), 3.32 (s, br, 4H, piperazine N(CH2)2), 3.55 (s, 2H, NCH2), 3.65 (s, 2H, NCH2), 3.71 (s, br, 4H, piperazine N(CH2)2), 7.46 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5), 8.11 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.13 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2), 13.34 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:36](Br)[CH:37]=[CH2:38]>O1CCCC1>[CH2:38]([C@H:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:10][C@@H:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:37]=[CH2:36]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 719 mg (2.00 mmol) di-tert-butyl N-(tert-butoxycarbonyl)-L-glutamate in tetrahydrofuran (12 mL) at −78° C., lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1.0 M in tetrahydrofuran, 4.40 mL) was added dropwise. The solution was stirred for 30 min, then allyl bromide (0.52 mL, 6.00 mmol) was added dropwise. The reaction was stirred at −78° C. overnight and then quenched at −10° C. by the addition of 10 mL of 2 N aqueous hydrogen chloride. The mixture was warmed to room temperature poured into 10 mL 1 N aqueous hydrogen chloride and extracted with dichloromethane (3×30 mL). The organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified on silica gel using a hexane/ethyl acetate gradient, and the appropriate fractions were combined and concentrated.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1Cl>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[CH:10]=[CH:9]2)([O-:5])=[O:4]
Reactant: ClC1CCCCO1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2C2CCCCO2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
6.3 g of 55% NaH are added, at 0° C., under an argon atmosphere, to 20 g of 5-nitroindole in solution in 200 ml of dimethylformamide. After stirring for 15 minutes at 0° C., 27.1 g of tetrahydropyranyl chloride are added to the reaction mixture. After stirring for 24 hours at room temperature, the reaction mixture is poured onto 1200 ml of ice-cold water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a 4/1 (v/v) cyclohexane/ethyl acetate mixture, to provide 19 g of 5-nitro-1-tetrahydropyran-2-ylindole. 1H NMR (DMSO): 1.34-2.12 (m, 6H), 3.67-4.48 (m, 2H), 5.70 (dd, J=2.0, 10.2, 1H), 6.75 (d, J=3.4, 1H), 7.72-7.76 (m, 2H), 8.02 (dd, J=2.2, 9.2, 1H), 8.54 (d, J=2.2, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:19]=3)[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[N:23]=[CH:22][N:21]=[C:20]([C:24](=[O:30])[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)C(=O)N(C)C)ncn3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1c[nH]c2ncc(-c3cc(C(=O)C(=O)N(C)C)ncn3)cc12
Temperature: 25 °C
Yield: 87.7 %

Procedure:
2-{6-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-2-oxo-acetamide (100 mg, 0.179 mmole) in methanol (3.6 mL) was cooled to 0° C. in an ice bath. Potassium hydroxide (aqueous 50% w/v, 0.06 mL) was added, the solution removed from the ice bath, maintained at ambient temperature for 15 hrs, and quenched with acetic acid (0.06 mL). The resulting solution was concentrated to remove all volatile organics, dissolved in ethyl acetate (10 mL), washed with sodium bicarbonate (5 mL), then with water (5 mL), then with brine (5 mL), and dried over magnesium sulfate. The solution was filtered and concentrated to dryness to afford 2-{6-[3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-2-oxo-acetamide (63 mg, 72%) as a yellow solid which was used without further purification. MS: m/z 402.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:27]C(=O)OC(C)(C)C)[C:10](=[O:26])[NH:11][C:12]2[CH:13]=[C:14]3[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:16]4=[CH:17][NH:18][C:19]([CH:20]=2)=[C:15]34)=[CH:4][CH:3]=1.[ClH:35]>O1CCOCC1>[ClH:35].[NH2:27][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:10]([NH:11][C:12]1[CH:13]=[C:14]2[C:24](=[O:25])[NH:23][N:22]=[CH:21][C:16]3=[CH:17][NH:18][C:19]([CH:20]=1)=[C:15]23)=[O:26]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(F)cc1)C(=O)Nc1cc2c3c(c[nH]c3c1)C=NNC2=O
Yield: 80 %

Procedure:
Preparation of example 194 from the title compound of Example 157 (48 mg, 0.10 mmol) and 4M HCl in dioxane (10 mL) was carried out analogously to Example 91. Isolation, also in an analogous manner afforded the title compound (34 mg, 0.08 mmol) as an orange/yellow powder in 80% yield.
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:10])=O>>[C:8]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]c1ccccc1
Reactant: O=C=O
Product: O=C(c1ccccc1)c1ccccc1
Yield: 70 %

Procedure:
In the preferred embodiment the chemical cocktail of the invention is a low-cost solution of an organometallic compound which rapidly absorbs and reacts with gaseous carbon dioxide to form benzophenone--a compound which has well separated infrared absorption bands when labeled in the carbonyl position with 13C or 12C. Exemplary of organometallic compounds, which in solution react with carbon dioxide to form benzophenone, are phenyl lithium and phenyl magnesium halides. M. I. Volpin and I. S. Kolomnikov, "The Reactions of Organometallic Compounds with Carbon Dioxide", Organomet. React. (1975) p. 320 and H. Gilman and P. R. VanEss, JACS, 55, 1258 (1933), the teachings of which are incorporated herein by reference, report that a 70% yield of benzophenone can be obtained by passing gaseous carbon dioxide through a phenyl lithium solution: ##STR1##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10]CC[Si](C)(C)C)[CH:7]=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.C(OCC)(=O)C>O1CCCC1>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[C:6]([C:17]([F:19])([F:20])[F:18])[CH:7]=[C:8]([SH:10])[CH:9]=1
Reactant: COC(=O)c1cc(SCC[Si](C)(C)C)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(S)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-trifluoromethyl-5-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester (580 mg, 1.72 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 11.6 mL, 11.6 mmol) and the yellow solution was stirred at room temperature for 1 hour. The reaction mixture was poured on aqueous 1M hydrochloric acid (30 mL) and ethyl acetate (30 mL) and the layers were separated. The aqueous layer was extracted a second time with ethyl acetate (30 mL). The organic layers were washed with 30 mL brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 0:100). Yellow solid (295 mg, 72%). MS (ESI−): m/z=235.01 ([M−H]−).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:69])[CH2:33][CH2:34][CH2:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([S:45][C@@H:46]3[O:63][C@H:62]([CH2:64][O:65]C(=O)C)[C@@H:57]([O:58]C(=O)C)[C@H:52]([O:53]C(=O)C)[C@H:47]3[O:48]C(=O)C)=[CH:41][CH:40]=2)=[O:37])=[CH:27][CH:26]=1)(=O)C>N>[C@@H:6]1([S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:69])[CH2:33][CH2:34][CH2:35][C:36]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([S:45][C@@H:46]4[O:63][C@H:62]([CH2:64][OH:65])[C@@H:57]([OH:58])[C@H:52]([OH:53])[C@H:47]4[OH:48])=[CH:43][CH:44]=3)=[O:37])=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(NC(=O)CCCC(=O)Nc3ccc(S[C@@H]4O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)cc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: O=C(CCCC(=O)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1)Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Reaction time: 2 h
Yield: 54.4 %

Procedure:
To 4.0 g of N,N'-bis[4-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thio]phenyl]pentanediamide was added 500 ml of ammonia saturated methanol at 0° C. The solution was kept at 0° C. for 2 hours, then at ambient temperature overnight and taken to dryness in vacuo. The residue was triturated with 20 ml of absolute ethanol and the resulting solid was collected, giving 1.45 g of the desired intermediate as an amorphous solid.
Reaction SMILES: [NH:1](C(=O)C(NC1C=CC(N2CCOCC2)=CC=1)=O)[NH2:2].[Cl:20][C:21]1[CH:22]=[C:23]([NH:34][C:35](=[O:40])[C:36](OC)=[O:37])[CH:24]=[C:25]([Cl:33])[C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:34][C:35](=[O:40])[C:36]([NH:1][NH2:2])=[O:37])[CH:24]=[C:25]([Cl:33])[C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: NNC(=O)C(=O)Nc1ccc(N2CCOCC2)cc1
Reactant: COC(=O)C(=O)Nc1cc(Cl)c(N2CCOCC2)c(Cl)c1
Product: NNC(=O)C(=O)Nc1cc(Cl)c(N2CCOCC2)c(Cl)c1

Procedure:
Following the general procedure of Intermediate 18, using methyl [(3,5-dichloro-4-morpholin-4-ylphenyl)amino](oxo)acetate as starting material, the title compound (Intermediate 100) was obtained; 1H NMR δ 3.08 (4H, t), 3.67 (4H, t), 4.62 (2H, s), 7.93 (2H, s), 10.31 (1H, broad s), 10.83 (1H, broad s); MS m/e MH+ 333.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2]>C1(C)C=CC=CC=1.COC(O)C>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH:1]=[N:3][CH:4]=[N:5]3)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(N)ccc21
Agent: COC(C)O
Solvent: Cc1ccccc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(-n3cncn3)ccc21

Procedure:
1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-amino-1H-benzimidazole (274 mg) is treated with N,N-dimethylformamide azine hydrochloride (1 eq) in toluene (10 mL) and methoxyethanol (10 mL) and refluxed for 6 h. After cooling and concentrating, the residue is treated with water and extracted with dichloromethane (2×). The aqueous layer is adjusted to pH 8 with aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic extracts are washed with saturated aqueous sodium chloride, dried (MgSO4), concentrated, purified by preparative silica gel chromatography, and triturated with ether to afford 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-(1,2,4-triazol-1-yl)-1H-benzimidazole, which is converted to the hydrochloride salt in ethyl acetate. LCMS MH+ 406.2.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:40])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccn4)ccc3n2C)cc1
Yield: 21 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-methoxycarbonylethyl)amide hydrochloride and n-heptyl chloroformate. Yield: 21% of theory, C34H41N7O5 (627.8); Rf value: 0.60 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=628; (M+H+Na)++=325.7; (M+2H)++=314.7.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([N:28]4[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29]4)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: OC1CCNC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCC(O)C4)cc3)cc12

Procedure:
1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2yl)ethyl)phenyl)ethyl)pyrrolidin-3-ol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and pyrrolidin-3-ol following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (20%). 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.76 (s, 1H), 8.72 (s, 1H), 8.29 (d, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.33-7.38 (m, 3H), 4.41 (m, 2H), 3.77 (m, 2H), 3.33 (t, 2H), 3.21 (t, 2H), 3.19 (m, 2H), 3.10 (m, 2H), 2.10 (s, 3H), 1.75 (d, 3H). LRMS [M+H]=427.2
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.Br[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)[CH2:15][CH3:16].CC(C1C(=O)OC2C(C=1O)=CC=CC=2)(C)C1C=CC=CC=1>C(Cl)Cl>[Br:23][C:19]1[CH:18]=[C:17]([CH:14]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:15][CH3:16])[CH:22]=[CH:21][CH:20]=1
Reactant: CCC(Br)c1cccc(Br)c1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: CC(C)(c1ccccc1)c1c(O)c2ccccc2oc1=O
Solvent: ClCCl
Product: CCC(c1cccc(Br)c1)c1c(O)c2ccccc2oc1=O
Temperature: 175 °C

Procedure:
A mixture of 4-hydroxycoumarin (898 mg) and 1-bromo-1-(3-bromophenyl)propane of Preparation 39 (3.08 g) under nitrogen is sealed in a screw-cap vial and placed in an oil bath at 100° C. The mixture is heated to 175° C. over approximately 45 rain, and the resulting melt is stirred at this temperature for 45 rain, cooled to RT, diluted with methylene chloride (45 mL), washed with water (10 mL) and saline (10 mL), dried over sodium sulfate, and concentrated under reduced pressure to give a residue which is then chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of ethyl acetate/hexane (15/85-60/40). Pooling of fractions with an Rf =0.20 by TLC (ethyl acetate/hexane, 50/50) and removal of solvent gives the title compound.
Reaction SMILES: [C:1]1([CH:7]2[C:11](=[S:12])[NH:10][N:9]=[C:8]2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C:26]2[C:27](C3C=CC(C)=CC=3)=[N:28]NC=2SSC2NN=C(C3C=CC(C)=CC=3)C=2C2C=CC=CC=2)C=CC=CC=1.BrCC#N.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:9][NH:10][C:11]=2[S:12][CH2:26][C:27]#[N:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2=NNC(=S)C2c2ccccc2)cc1
Reactant: Cc1ccc(-c2n[nH]c(SSc3[nH]nc(-c4ccc(C)cc4)c3-c3ccccc3)c2-c2ccccc2)cc1
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2n[nH]c(SCC#N)c2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 4-phenyl-3-p-tolyl-1H-pyrazole-5(4H)-thione and 1,2-bis(4-phenyl-3-p-tolyl-1H-pyrazol-5-yl)disulfane (0.500 g, 1.88 mmol) in DMF (12.5 mL) was added 2-bromoacetonitrile (0.125 mL, 1.88 mmol) and K2CO3 (0.259 g, 1.88 mmol). The reaction was stirred at 25° C. for 72 h, quenched with water (40.0 mL) and extracted with EtOAc (4×50.0 mL) and washed with brine. The combined organics were dried over MgSO4, filtered, and concentrated to give the title compound as a yellow oil (0.547 g). LCMS m/z=306.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C([O-])(O)=O.[Na+]>C1COCC1>[O:33]=[C:24]1[C:25]2[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:28])[N:23]1[CH2:22][CH:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)Cc1ccsc1
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CN1C(=O)c2ccccc2C1=O)c1ccsc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To pure methyl 2-(thiophen-3-yl)acetate (E41) in THF cooled to −78° C. was added LiHMDS, and the solution stirred at −78° C. for 30 min. Then N-(bromomethyl)phthalimide was added directly, and the solution was allowed to warm to 0° C. The mixture was poured into NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 0-40% EtOAc/Hex) gave pure methyl 3-(1,3-dioxoisoindolin-2-yl)-2-(thiophen-3-yl)propanoate (E45).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[C:10]#[N:11].O.[NH2:13][NH2:14]>C(O)C>[NH2:11][C:10]1[C:3]2[C:4]([C:8]#[N:9])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:14][N:13]=1
Reactant: N#Cc1cccc(F)c1C#N
Reactant: NN
Solvent: CCO
Solvent: O
Product: N#Cc1cccc2[nH]nc(N)c12
Temperature: 70 °C
Yield: 86.9 %

Procedure:
3-Fluoro-1,2-benzenedicarbonitrile (APIN) (5 g, 34.2 mmol) was dissolved in ethanol (80 mL) and hydrazine monohydrate (4.98 mL, 103 mmol) was added to the solution. The reaction was heated at 70° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (100 mL). The aqueous layers were extracted with ethyl acetate (200 mL). Organic layers were combined, dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compound (4.7 g, 87%) as a yellow solid. LCMS (System A) RT=0.53 min, ES+ve m/z 159 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[C:8]([CH:13]([CH3:15])[CH3:14])[O:9]2)=[CH:4][CH:3]=1.Cl.[F:25][C:26]([F:31])([F:30])[C:27](O)=O>C(OCC)(=O)C>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:7]2[C:6](=[O:23])[C:5]3[CH:4]=[CH:3][C:2]4[NH:1][C:27]([C:26]([F:31])([F:30])[F:25])=[N:12][C:11]=4[C:10]=3[O:9][C:8]=2[CH:13]([CH3:14])[CH3:15])=[CH:21][CH:20]=1
Reactant: CC(C)c1oc2c(N)c(N)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)c1oc2c(ccc3[nH]c(C(F)(F)F)nc32)c(=O)c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
7,8-Diamino-3-(4-chlorophenyl)-2-isopropyl-chromen-4-one (80 mg, 0.243 mmol) is dissolved in trifluoroacetic acid (1.4 ml), dilute hydrochloric acid (2M, 0.1 ml) is added, and the mixture is heated at 110° C. for 2.5 h. The reaction mixture is cooled to room temperature, diluted with ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (2×40 ml), water (40 ml) and saturated brine (40 ml). The organic layer is dried (MgSO4), filtered and evaporated to give a solid. This is triturated with dichloromethane containing a few drops of ethyl acetate and filtered to give a colourless powder.