Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]2[N:11]3[C:12](=[O:24])[NH:13][C:14]3[C:15]2=[N:21][NH:22][CH:23]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)CCC.[C:30](#[N:34])[CH2:31][CH2:32]C.C1(N)CC1>C1(C)C=CC=CC=1>[CH:30]1([NH:34][C:12]([NH:13][C:14]2[C:15]([C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:8]([CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:9][C:10]=4[N:11]=3)=[N:21][NH:22][CH:23]=2)=[O:24])[CH2:32][CH2:31]1
Reactant: O=c1[nH]c2c[nH]nc2c2nc3ccc(CN4CCOCC4)cc3n12
Reactant: CCCC#N
Agent: NC1CC1
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)NC1CC1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
7-Morpholin-4-ylmethyl-2,4-dihydro-1,2,4,5a,10-pentaaza-cyclopenta[a]fluoren-5-one (1.0 wt, prepared as outlined in Example 66 of WO 2006/070195) and a solvent such as n-butanol, butyronitrile, glycol or toluene (3.0 vol) can be charged to a flange flask equipped with a mechanical stirrer, condenser and thermometer. Cyclopropylamine (0.351 wt) can be added at temperature such as 15 to 30° C. under an inert atmosphere e.g. nitrogen. The contents can be heated to 40 to 105° C., in particular 40-80° C. and stirred at this temperature for 16 to 24 hours. Reaction completion can be determined by 1H NMR analysis. The reaction mixture can then be cooled to 10 to 20° C. The product can then be isolated by organic-aqueous extraction method as outlined above in Example 66, or an alternative method of isolation may be employed such as the addition of an anti-solvent, for example n-heptanes, to the reaction mixture. This could allow the reaction product to precipitate with subsequent isolation by filtration. The solid can then be dried under vacuum at 35 to 45° C. to yield 1-cyclopropyl-3-[3-(5-morpholin-4-ylmethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-urea. At this stage the solid can be purified by recrystallisation from an appropriate solvent, preferably a Class 2 or 3 solvent1. In addition, alternative methods of purification aside from recrystallisation may be employed for purification of the product such as flash column chromatography or filtration through a plug of silica gel or reverse-phase silica gel. 1 Class 3 and Class 2 solvents are as outlined Q3C - Tables and List in Guidance for Industry Q3C Impurities: Residual Solvents (November 2003, CDER, CBER, FDA, ICH) and as further outlined in Impurities: Guideline for Residual Solvents (1997, ICH).
Reaction SMILES: [NH2:1][C:2](=[N:42][OH:43])[C:3]1[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([F:40])[CH:37]=3)[CH2:32]2)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=1.[O-2].[Mg+2].[Cl:46][CH2:47][C:48](Cl)=O>O1CCOCC1.C(OCC)(=O)C>[Cl:46][CH2:47][C:48]1[O:43][N:42]=[C:2]([C:3]2[CH:4]=[CH:5][C:6]([CH3:41])=[C:7]([N:9]([CH2:26][C:27]([N:29]([N:31]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([F:40])[CH:37]=4)[CH2:32]3)[CH3:30])=[O:28])[CH2:10][C:11]([NH:13][CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:17][CH3:18])=[O:12])[CH:8]=2)[N:1]=1
Reactant: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(C(N)=NO)ccc1C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)CCl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCN(CCNC(=O)CN(CC(=O)N(C)N1Cc2ccc(F)cc2C1)c1cc(-c2noc(CCl)n2)ccc1C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
The compound (4.82 g, 8.04 mmol) of Example 290, step B was dissolved in 1,4-dioxane (70 ml), magnesium oxide (355 mg, 8.81 mmol) and chloroacetyl chloride (0.67 ml, 8.42 mmol) were added at room temperature, and the mixture was stirred at 100° C. for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (3.40 g, yield 64%) as a pale-yellow amorphous solid
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl[C:27]1[N:32]=[C:31]([NH:33][C:34]([C:36]2([C:39]3[CH:49]=[CH:48][C:42]4[O:43][C:44]([F:47])([F:46])[O:45][C:41]=4[CH:40]=3)[CH2:38][CH2:37]2)=[O:35])[CH:30]=[CH:29][C:28]=1[CH3:50]>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:47][C:44]1([F:46])[O:43][C:42]2[CH:48]=[CH:49][C:39]([C:36]3([C:34]([NH:33][C:31]4[CH:30]=[CH:29][C:28]([CH3:50])=[C:27]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([C:3]([OH:8])([C:4]([F:6])([F:5])[F:7])[C:2]([F:1])([F:25])[F:24])[CH:10]=5)[N:32]=4)=[O:35])[CH2:38][CH2:37]3)=[CH:40][C:41]=2[O:45]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2cccc(C(O)(C(F)(F)F)C(F)(F)F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Temperature: 120 °C
Yield: 76.6 %

Procedure:
To a mixture of 1,1,1,3,3,3-hexafluoro-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (50 mg, 0.13 mmol) and N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (37 mg, 0.10 mmol) in DME (1 mL) and 2 M Na2CO3 (0.1 mL) was added Pd(PPh3)4 (6 mg, 0.005 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The mixture was partitioned between ethyl acetate and H2O, and the aqueous layer was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography (20-40% ethyl acetate-hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-(3-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-5-methylpyridin-2-yl)cyclopropane-carboxamide (44 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 8.01 (d; J=8.4 Hz, 1H), 7.71 (s, 1H), 7.66-7.62 (m, 2H), 7.53-7.43 (m, 3H), 7.15 (td, J=8.8, 1.7 Hz, 2H), 7.00 (d, J=8.2 Hz, 1H), 2.19 (s, 3H), 1.68 (q, J=3.6 Hz, 2H), 1.10 (q, J=3.6 Hz, 2H). MS (ESI) m/e (M+H+) 575.3.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)ccc1OCc1ccccc1

Procedure:
To a solution of methyl 5-chlorosalicylate (5.58 g, 0.03 mol) in 20 ml of dry acetone were added anhydrous K2CO3 (4.55 g, 0.033 mol) and benzylbromide (5.64 g, 0.033 mol). The resulting solution was refluxed for 5 h and the solvent evaporated under reduced pressure. The residue was partitioned between ether and water. The ether layer was washed with 10% aqueous NaOH solution and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was recrystallized from absolute ethanol affording 7.6 g (91.7%) of methyl 5-chloro-2-phenylmethoxybenzoate as white crystals: mp 54.5°-55° C.; IR (KBr) 1740 (ester) cm-1 ; NMR (CDCl3, 90 MHz) δ 3.90 (s, 3H, CO2CH3), 5.16 (s, 2H, OCH2Ph), 6.93 (d, 1H, ArH, J=8.9 Hz), 7.20-7.55 (m, 6H, ArH), 7.79 (d, 1H, ArH, J=2.9 Hz). Anal calcd. for (C15H13ClO3): C, 65.11; H, 4.73; Cl, 12.81. Found: C, 65.33; H, 4.88; Cl, 13.08.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][C:22]([CH3:31])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)O)(C)(C)C>ClCCl>[CH3:31][C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][CH2:16][NH2:15])[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(O)NCCCN1CCC(C)(c2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(c2ccccc2)CCN(CCCN)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
Trifluoroacetic acid (1 mL) was added to tert-butoxy{[3-(4-methyl-4-phenyl-1-piperdinyl)propyl]-amino}methanol (0.500 g, 1.51 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The solution was concentrated, neutralized with 10% KOH solution and extracted with dichloromethane (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated, giving 0.340 g (98%) of 3-(4-methyl-4-phenyl-1-piperdinyl)propylamine which was used without further purification in the subsequent step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[S:41](Cl)(=[O:43])=[O:42])[CH:34]=[CH:33][CH:32]=1>>[C:25]1([S:22]([NH:21][C:3]2[CH:4]=[C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][S:41]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[N:31]=[CH:32][CH:33]=[CH:34]3)(=[O:42])=[O:43])(=[O:24])=[O:23])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1cccc2cccnc12)c1ccccc1

Procedure:
N-[2-[(Phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]-8-quinolinesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 8-quinolinesulfonylchloride (54 mg, 0.239 mmol) according to general method 3 to give 50 mg of a purple solid. MS (posES-FIA) m/z=Found: 524.2; Calcd: 524.13; 1H NMR δ 9.34 (dd, 1H), 8.79 (dd, 1H), 8.37 (dd, 1H), 8.25 (dd, 1H), 7.92 (dd, 1H), 7.73 (t, 1H), 7.57-7.40 (m, 5H), 7.17 (d, 1H), 6.71 (dd, 1H), 6.14 (d, 1H), 3.23-3.08 (m, 8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([N+:12]([O-])=O)=[CH:5][C:4]=1[O:15][CH3:16].[Br:17][CH2:18][C:19](=O)[C:20](=O)[CH3:21]>C(O)(=O)C.[Pd]>[Br:17][CH2:18][C:19]1[C:20]([CH3:21])=[N:9][C:7]2[C:6](=[CH:5][C:4]([O:15][CH3:16])=[C:3]([O:2][CH3:1])[CH:8]=2)[N:12]=1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Reactant: CC(=O)C(=O)CBr
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2nc(C)c(CBr)nc2cc1OC

Procedure:
11.4 g (50 mmols) of 1,2-dimethoxy-4,5-dinitrobenzene are dissolved in 100 ml of glacial acetic acid and, after adding 0.6 g of 10% strength palladium-on-characoal, hydrogenated under normal pressure; the temperature can rise to 60° C. during the hydrogenation. Consumption of hydrogen: 7,300 ml (100% of theory). The catalyst is filtered off and the filtrate is cooled, under nitrogen, to 5° to 10° C. Whilst stirring well, 9 g (55 mmols) of 1-bromo-2,3-butanedione are added dropwise at 10° C. The solution is stirred for 60 minutes, during which time the desired product starts to precipitate out. The reaction mixture is discharged into 300 ml of cold water and the mixture is stirred for 10 minutes. The product which has precipitated is filtered off, washed with water and dried in vacuo at 60° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[ClH:18].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21]([CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=1)=[O:29])[CH2:20]2.[OH-].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:18].[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21]([CH2:27][C:28]([NH:30][C:31]1[CH:32]=[C:33]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)[CH:34]=[CH:35][CH:36]=1)=[O:29])[CH2:20]2
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C(CC1CN2CCC1CC2)Nc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CC1CN2CCC1CC2)Nc1cccc(-c2ccc(CO)cc2)c1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
24.0 mg (0.16 mmol) of 4-(hydroxymethyl)phenylboronic acid, 0.17 ml (0.34 mmol) of 2M aqueous sodium carbonate solution and 5.8 mg (0.01 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride are added to a solution of 75 mg (0.16 mmol) of 2-(1-azabicyclo[2.2.2]oct-3-yl)-N-(3-bromophenyl)acetamide hydrochloride in 1 ml of DMF. The reaction mixture is stirred at 80° C. for 14 h. A further 24.0 mg (0.16 mmol) of 4-(hydroxymethyl)phenylboronic acid, 23.2 mg (0.03 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 0.48 ml (0.48 mmol) of 1M sodium hydroxide solution are added. The mixture is then heated at 80° C. for a further 12 h. After the reaction is complete, the mixture is cooled, filtered through silica gel and then purified by preparative HPLC. The product fractions are concentrated, taken up in methanol, mixed with 4M HCl in dioxane and again concentrated. Drying under high vacuum results in 25.9 mg (39.8% of theory) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[N+:13]([O-:15])=[O:14])=O.[CH3:16][CH2:17][O:18][C:19]([CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:20]>ClCCl>[CH2:17]([O:18][C:19](/[CH:21]=[CH:1]/[C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[N+:13]([O-:15])=[O:14])=[O:20])[CH3:16]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cnc2c([N+](=O)[O-])cccc2c1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc2c([N+](=O)[O-])cccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
A mixture of 3-formyl-8-nitroquinoline (65 mg) and ethyl (triphenylphosphoranilidene)acetate (123 mg) in dichloromethane (3 ml) was stirred for 2 hours at ambient temperature. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 3-((E)-2-ethoxycarbonylvinyl)-8-nitroquinoline (92 mg).
Reaction SMILES: C(O)CCCCCCCO.BrCC1C2C(=CC=CC=2)C=CC=1.[C:23]1([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][OH:43])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C1(COCCCCCCCC(O)=O)C2C(=CC=CC=2)C=CC=1.Cl.Cl.[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH2:83])[CH2:79][N:80]([CH3:82])[CH3:81])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>>[CH2:68]([O:75][C:76](=[O:84])[CH2:77][C@@H:78]([NH:83][C:42](=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:34][CH2:33][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH2:79][N:80]([CH3:81])[CH3:82])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Reactant: OCCCCCCCCOCc1cccc2ccccc12
Agent: BrCc1cccc2ccccc12
Agent: Cl
Agent: O=C(O)CCCCCCCOCc1cccc2ccccc12
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1cccc2ccccc12

Procedure:
The title compound, m/e=427.1 ([M−H]−), was produced in analogy with example 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 1-bromomethyl-naphthalene, leading to 8-(naphthalen-1-ylmethoxy)-octan-1-ol, which was oxidized in step 2 to 8-(naphthalen-1-ylmethoxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(naphthalen-1-ylmethoxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: O=[C:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])[CH2:3][N:4]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.C([O-])(=O)C.[NH4+:31].C(OCC)(=O)C.[OH-].[Na+]>C(O)(=O)C>[C:21]1([CH3:26])[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:31]=[C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]2[CH:3]=1
Reactant: [NH4+]
Reactant: Cc1ccccc1C(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Temperature: 120 °C
Reaction time: 48 h
Yield: 52.9 %

Procedure:
To a solution of 5-(2-oxo-2-(o-tolyl)ethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.6 g, 1 eq.) in acetic acid (10 mL) was added ammonium acetate (2.7 g, 20 eq.). The reaction was stirred at 120° C. for 48 hours. The reaction was poured onto water (50 mL) and ethyl acetate (150 mL). The pH was adjusted to 9 by the addition of NaOH 1N. The phases were separated and washed with water (1×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10% ethyl acetate in dichloromethane) gave the 2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.3 g, 53%). M.p.: 215-217° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.60 (s, 1H), 8.18 (dd, JA=4.4 Hz, JB=1.2 Hz, 1H), 7.99 (dd, JA=8.0 Hz, JB=1.2 Hz, 1H), 7.91-7.85 (m, 2H), 7.82 (s, 1H), 7.34-7.20 (m, 5H), 7.14 (dd, JA=8.0 Hz, JB=4.8 Hz, 1H), 7.05 (t, J=8.4 Hz, 1H), 2.56 (s, 3H); LCMS: 325 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[Mg].C1O[C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16]C1>O1CCCC1>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([C:20]3[CH2:21][CH2:22][C:17](=[O:16])[CH2:18][CH:19]=3)[CH:3]=[CH:4][C:5]=2[O:9]1
Reactant: CC1(C)Cc2cc(Br)ccc2O1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C3=CCC(=O)CC3)ccc2O1

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 7, using 9.2 grams (0.040 mole) of 5-bromo-2,3-dihydro-2,2-dimethylbenzofuran, 1.1 grams (0.044 mole) of magnesium turnings, and 6.2 grams (0.040 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 70 mL of tetrahydrofuran, yielding 1-(2,3-dihydro-2,2-dimethylbenzofuran-5-yl)-1-cyclohexen-4-one.
Reaction SMILES: FC(F)OC1C=CC=CC=1CS(CC(NC(N1CCOCC1)=O)C(O)=O)(=O)=O.FC(F)O[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][S:39]([CH2:42][CH:43]([NH:60][C:61]([N:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)=[O:62])[C:44](=[O:59])[NH:45][C:46]([CH3:58])([CH3:57])[C:47](=[O:56])[C:48](=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)(=[O:41])=[O:40]>>[OH:56][CH:47]([C:48](=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:46]([NH:45][C:44]([CH:43]([NH:60][C:61]([N:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1)=[O:62])[CH2:42][S:39]([CH2:38][C:33]1[CH:32]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:41])=[O:40])=[O:59])([CH3:57])[CH3:58]
Reactant: CC(C)(NC(=O)C(CS(=O)(=O)Cc1ccccc1OC(F)F)NC(=O)N1CCOCC1)C(=O)C(=O)c1ccccc1
Agent: O=C(O)C(CS(=O)(=O)Cc1ccccc1OC(F)F)NC(=O)N1CCOCC1
Product: CC(C)(NC(=O)C(CS(=O)(=O)Cc1ccccc1)NC(=O)N1CCOCC1)C(O)C(=O)c1ccccc1

Procedure:
By proceeding in a similar manner to Example 13 but using 3-(2-difluoromethoxy-phenylmethanesulfonyl)-2-[(morpholine-4-carbonyl)-amino]-propionic acid in step 3 there was prepared morpholine-4-carboxylic acid [2-(2-difluoromethoxy-phenylmethanesulfonyl)-1-(1,1-dimethyl-2,3-dioxo-3-phenyl-propylcarbamoyl)-ethyl]-amide. LC-MS: elution time=3.95 min. 593.4(M−1), 596.2(M+1). (MS: API 150EX. LC: HP Agilent 1100 Series. Column: Phenomenex, 5u ODS3 100A 100×3 mm.; Flow Rate: 2 ml/min. Two solvent gradient: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH. Solvent B, 99% actonitrile, 1% water, 0.1% AcOH. Gradient from 100% A, 0% B to 0% A, 100% B from t=0 to t=6 min. Then gradient back to 100% A, 0% B from t=7 to t=15 min.)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:13][CH:12]=2)=[O:9])[CH2:3][CH2:2]1)(=[O:25])=[O:24]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)NC1CCNCC1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Intermediate 42 (152 mg, 0.5 mmol) was reacted with methanesulfonyl chloride by Method E. Recrystallization from EtOAc:acetone afforded compound 55 (160 mg, 84%) as a white solid: Mp 233-234° C. 1H NMR (500 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H), 3.64-3.55 (m, 1H), 3.47 (d, J=12.2 Hz, 2H), 2.91-2.84 (m, 5H), 1.94-1.88 (m, 2H), 1.50-1.40 (m, 2H). Purity 98%. HRMS calculated for C14H18F3N3O4S−H+ 380.0892. found (ESI(−), [M−H]) 380.0931.
Reaction SMILES: [N+](=[C:3]1[N:7]=[C:6]2[C:8]([CH3:17])=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([CH2:12][CH3:13])[C:5]2=[N:4]1)=[N-].N([O-])=O.[Na+].[F:22][B-](F)(F)F.[H+]>>[CH2:12]([C:11]1[C:5]2[NH:4][C:3]([F:22])=[N:7][C:6]=2[C:8]([CH3:17])=[CH:9][C:10]=1[N+:14]([O-:16])=[O:15])[CH3:13]
Reactant: CCc1c([N+](=O)[O-])cc(C)c2c1=NC(=[N+]=[N-])N=2
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: CCc1c([N+](=O)[O-])cc(C)c2nc(F)[nH]c12

Procedure:
2,4-Dinitro-3-ethyl-6-methylaniline (see Example 2) is treated with sodium sulfide to afford 1,2-diamino-3-ethyl-6-methyl-4-nitrobenzene. Treatment with cyanogen bromide affords to 2-amino-4-ethyl-7-methyl-5-nitrobenzimidazole. This is converted to 2-diazo-4-ethyl-7-methyl-5-nitrobenzimidazole tetrafuoroborate with sodium nitrite and tetrafluoroboric acid. Thermal decomposition of the diazonium salt gives 4-ethyl-2-fluoro-7-methyl-5-nitrobenzimidazole. Conversion to 4-ethyl-2-fluoro-5-(2-imidazolinylamino)benzimidazole is completed according to Scheme 5.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=2[C:16]([F:19])([F:18])[F:17])[CH:4]=[CH:5][N:6]=1>CO.[Ni]>[CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=2[C:16]([F:19])([F:17])[F:18])[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ni]
Solvent: CO
Product: Cc1nccn1-c1ccc(N)cc1C(F)(F)F

Procedure:
The title compound is generated from 2-methyl-1-(4-nitro-2-trifluoromethyl-phenyl)-1H-imidazole (Stage 152.2) by hydrogenation in the presence of Raney-Ni in MeOH during 14 h at rt: Rf (MeOH/CH2Cl2=1:5): 0.42; M+H=242.0; m.p.=217-219° C.