Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[S:25][CH:26]=[CH:27][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[CH3:13][O:12][C:11]1[C:2]([O:1][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[C:3]2[C:8](=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=1)[N:7]=[CH:6][CH:5]=[C:4]2[CH3:17]
Reactant: BrCCCCCc1cccs1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1cccs1

Procedure:
To a mechanically stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (WRAIR; 5.67 g, 0.023 mol), 1-bromo-5-(2-thienyl) pentane from previous step a (5.32 g, 0.023 mol) and HMPA (40 ml), at 115°-120° C., was added dropwise, during 45 min, a solution of Et3N (5 ml) and propylene oxide (10 ml). The mixture was heated at 115°-120° C. for 5 hr, allowed to cool and extracted with a solution of pet. ether (20°-40° C.) and Et2O (1:1 v/v, 200 ml). The extract was washed with 10% NaOH solution (3×75 ml) and the combined basic washings were re-extracted with pet. ether (20°-40°) and Et2O solution (1:1 v/v, 2×100 ml). The combined organic layers were washed with H2O (2×100 ml), dried (K2CO3), and treated with carbon (Darco G-60). Solvent evaporation gave 6-methoxy-4-methyl-8-nitro-5-[5-(2-thienyl) pentoxy] quinoline as a yellow solid, 5.61 g (61%), mp 51°-54° C. This material was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][CH:14]([C:16]1[N:21]=[N:20][C:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:18][CH:17]=1)[CH3:15])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:15][C:14]1[N:13]=[C:11]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[N:20]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3cc4ccccc4n3C)nn2)cc1
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2ncc3c(C)nc(-c4cc5ccccc5n4C)n3n2)cc1
Yield: 7.5 %

Procedure:
Applying the Cyclization Procedure 2, using 1-methyl-N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-1H-indole-2-carboxamide (Intermediate 56) (151 mg, 0.38 mmol), pyridine (3.7 mL), 1,2,4 triazole (78 mg, 1.13 mmol) and phosphorus oxychloride (0.052+0.052 mL, 1.12 mmol), to afford 5-methyl-7-(1-methyl-1H-indol-2-yl)-N-[4-(methyloxy)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (11 mg) as a yellow solid. MS m/z 385 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2[O:12][C:11](C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:41]=[CH:40][CH:39]=[CH:38][C:26]=1[CH2:27][S:28]([N:31]1[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]1)(=[O:30])=[O:29]>>[CH:11]([OH:12])=[O:29].[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:41]=[CH:40][CH:39]=[CH:38][C:26]=3[CH2:27][S:28]([N:31]3[CH2:36][CH2:35][NH:34][C:33](=[O:37])[CH2:32]3)(=[O:30])=[O:29])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=C1CN(S(=O)(=O)Cc2ccccc2Br)CCN1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3CS(=O)(=O)N3CCNC(=O)C3)cc2F)cn1
Product: O=CO

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 4-((2-bromobenzyl)sulfonyl)piperazin-2-one. MS (ESI): mass calcd. for C21H20FN5O3S, 441.13; m/z found, 441.9 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.08 (d, J=1.3, 1H), 7.96 (m, 1H), 7.70-7.62 (m, 1H), 7.52-7.28 (m, 5H), 4.48 (s, 2H), 3.63 (s, 2H), 3.25 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:16]([CH3:27])[NH:15][C:14]=1[CH:28]=O>N1CCCC1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:28][C:14]1[NH:15][C:16]([CH3:27])=[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:13]=1[CH3:12]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Solvent: C1CCNC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1CCCN1CCOCC1
Temperature: 90 °C
Yield: 90 %

Procedure:
A mixture of 5-bromo-1,3-dihydroindol-2-one (212 mg, 1.0 mmol), 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (250 mg, 1.0 mmol) and 3 drops pyrrolidine in 2.0 ml of ethanol was refluxed at 90° C. for 4 hours and then cooled to room temperature. The precipitate was filtered, washed with cold ethanol and hexane and dried in a vacuum oven overnight to give 399.8 mg (90%) of 5-bromo-3-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydroindol-2-one as a red solid:
Reaction SMILES: CC[N:3]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:22]([C:25]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:26]=1N)([CH3:24])[CH3:23].[Br:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=O>CN(C=O)C>[Br:35][CH2:36][CH2:37][CH:38]([C:26]1[C:25]([CH:22]([CH3:24])[CH3:23])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:32]([CH3:34])[CH3:33])[C:39]([NH2:3])=[O:41]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C(O)CCCBr
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1C(CCBr)C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.9 %

Procedure:
WSC (2.3 g, 12 mmols) and HOBt (1.49 g, 15 mmols) were added to a DMF (30 ml) solution of 2,6-diisopropylaniline (1.97 g, 10 mmols) and 4-bromobutyric acid (2.71 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.04 g (32%) of 4-bromo-(2,6-diisopropylphenyl)butanamide as colorless needle-like crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:15][C:14]([NH:16][C:17](=[O:32])[CH2:18][C:19]2[N:20]=[C:21]([NH:24]C(=O)OC(C)(C)C)[S:22][CH:23]=2)=[N:13][CH:12]=1)([CH3:10])[CH3:9].C1(OC)C=CC=CC=1>C(Cl)Cl>[NH2:24][C:21]1[S:22][CH:23]=[C:19]([CH2:18][C:17]([NH:16][C:14]2[S:15][C:11]([CH:8]([CH3:10])[CH3:9])=[CH:12][N:13]=2)=[O:32])[N:20]=1
Reactant: CC(C)c1cnc(NC(=O)Cc2csc(NC(=O)OC(C)(C)C)n2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(C)c1cnc(NC(=O)Cc2csc(N)n2)s1

Procedure:
Trifluoroacetic acid (168 ml) was added to a solution of tert-butyl 4-{2-[(5-isopropyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,3-thiazol-2-ylcarbamate (22 g, 57.51 mmol) in CH2Cl2 (750 ml) and anisole (9.33 ml, 86.27 mmol) under ice-cooling.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:22])[C:10]3[NH:11][C:12]([Br:21])=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.O.C(#N)C>[Br:21][C:12]1[NH:11][C:10]2[C:9](=[O:22])[N:8]3[C:4]([CH2:3][CH2:2][NH:1][C:30]([NH:29][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:31])=[N:5][N:6]=[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=2[N:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCN)nnc12
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCNC(=O)Nc3ccccc3)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 3-(2-aminoethyl)-7-bromo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (62 mg, 0.17 mmol) and phenyl isocyanate (0.018 mL, 0.16 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and acetonitrile and then purified by preparative LCMS to give the desired product (about 80% conversion). LCMS calculated for C20H24BrN8O2 (M+H): 487.1; 489.1. found: 487.0, 489.0.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:7]([O:9]CC)=O)=[N:4][O:5][CH:6]=1.[N:12]1([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH2:26]/[CH:27]=[CH:28]\[CH2:29][NH2:30])[CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:7]([NH:30][CH2:29]/[CH:28]=[CH:27]\[CH2:26][O:25][C:21]2[CH:20]=[C:19]([CH2:18][N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:24]=[CH:23][N:22]=2)=[O:9])=[N:4][O:5][CH:6]=1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CCOC(=O)c1nocc1O
Solvent: Cc1ccccc1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1nocc1O
Yield: 30.8 %

Procedure:
375 mg of ethyl 4-hydroxy-3-isoxazolecarboxylate (prepared as described in Preparation 4) were added to a solution of 520 mg of 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine in 10 ml of toluene, and the resulting mixture was heated under reflux for 6 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:19 by volume mixture of methanol and ethyl acetate as the eluent, to give 228 mg (yield 31%) of the title compound as an oil.
Reaction SMILES: [OH-].[K+].[C:3]1([CH2:9][C:10]#[N:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N+:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)([O-])=[O:13].C(O)(=O)C>CO.O>[OH:13][N:12]=[C:15]1[S:16][C:17](=[C:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10]#[N:11])[CH:18]=[CH:19]1
Reactant: N#CCc1ccccc1
Reactant: O=[N+]([O-])c1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#CC(=C1C=CC(=NO)S1)c1ccccc1
Temperature: 0 °C
Yield: 37.4 %

Procedure:
14 g of KOH are dissolved in 50 ml of methanol. To the solution are added 7.1 ml (62 mmol) of phenylacetonitrile followed by 10 g (62 mmol) of 2-nitrothiophene dissolved in 30 ml of methanol. After the reaction mixture is stirred in the ice bath for 10 min, 200 ml of water are added with stirring. The resulting solution is acidified by addition of 55 ml of acetic acid in 50 ml of water, and extracted with ethyl acetate. The organic phase is washed with sodium chloride solution, and dried over MgSO4. After the solvent is distilled off, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:3), and recrystallization from toluene. 5.3 g (38%) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-phenyl-acetonitrile are obtained in the form of orange crystals having a melting point of 165° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][Br:25])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][C:32]1[S:36][CH:35]=[N:34][CH:33]=1>C(OCC)(=O)C>[Br-:25].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21]([CH:22]=[CH:23][CH2:24][N+:34]4[CH:33]=[C:32]([CH3:31])[S:36][CH:35]=4)=[O:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cncs1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Solvent: CCOC(C)=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CC[n+]1csc(C)c1
Product: [Br-]
Yield: 34 %

Procedure:
A solution of 0.5 g (1 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 0.6 g (6.1 mmol) of 5-methyl thiazole was refluxed for 4 hr. The mixture was diluted with ethyl acetate and cooled. Solid was collected and recrystallized from methanol-acetone-ethyl acetate to give 0.2 g of the title compound as a yellow powder: mass spectrum (electrospray, m/e): M+508.0, 509.9, (M+H)+2254.4, 255.1.
Reaction SMILES: [C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([OH:3])=O.[C:16](=O)=[O:17].C([N:21]([CH2:24]C)CC)C.C(Cl)(=O)C(C)(C)C.Cl.CNOC.Cl>ClCCl>[CH3:16][O:17][CH2:24][NH:21][C:1]([C@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:3]
Reactant: O=C=O
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CNOC
Agent: Cl
Solvent: ClCCl
Product: COCNC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
13.0 g (56.8 mmol) of 1,1-dimethylethyl (R)-2-carboxypyrrolidine-1-carboxylate and 190 ml of dichloromethane are placed in a 500 ml three-necked flask fitted with a thermometer and a 250 ml addition funnel. The mixture is cooled to −20° C. on a bath of cardice and 7.91 ml (57 mmol) of triethylamine are added, followed by 7.01 ml (56.8 mmol) of pivaloyl chloride. The mixture is stirred vigorously for 15 minutes at −10° C., the temperature is then allowed to rise to 0° C., and a solution of 11.07 g (113 mmol) of N,O-dimethylhydroxylamine hydrochloride and 17.4 ml (125 mmol) of triethylamine in 160 ml of dichloromethane is added dropwise. The reaction mixture is allowed to warm to room temperature over 120 minutes and is then cooled to 0° C. on an ice bath and 100 ml of a 0.1N hydrochloric acid solution are added. The organic phase is washed successively with 100 ml of 0.2M sodium hydroxide solution and with 200 ml of brine, and is then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a column of silica (elution solvent: 50% ethyl acetate in cyclohexane). 14.26 g (yield: 92%) of 1,1-dimethylethyl (R)-2-[(methoxymethylamino)carbonyl]pyrrolidine-1-carboxylate are obtained in the form of a colorless oil.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C@H:13]2[CH2:37][CH2:36][C@@:35]3([CH3:38])[C:15](=[CH:16][CH2:17][C@@H:18]4[C@@H:34]3[CH2:33][CH2:32][C@@:31]3([CH3:39])[C@H:19]4[CH2:20][CH2:21][C@@H:22]3[C@H:23]([CH3:30])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:14]2)C(=O)C2=CC=CC=C12.C(N)CCC>CO.C(Cl)(Cl)Cl>[CH3:29][CH:27]([CH2:26][CH2:25][CH2:24][C@H:23]([C@@H:22]1[C@:31]2([CH3:39])[C@H:19]([C@H:18]3[C@H:34]([CH2:33][CH2:32]2)[C@:35]2([CH3:38])[C:15]([CH2:14][C@@H:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])[CH2:37][CH2:36]2)=[CH:16][CH2:17]3)[CH2:20][CH2:21]1)[CH3:30])[CH3:28]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCN5C(=O)c6ccccc6C5=O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CO
Solvent: CCCCN
Solvent: ClC(Cl)Cl
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 43.1 %

Procedure:
A solution of 6-phthalimido-1-(5-cholesten-3β-yloxy)hexane (500 mg) and n-butylamine (5 ml) in methanol (10 ml) and chloroform (5 ml) is heated under reflux for 1 hour. The solution is evaporated in vacuo to a residue that is put on a column of silica gel and eluted with CHCl3 -MeOH-NH4OH 90:10:1 (v/v/v). The ninhydrin positive fractions are combined and evaporated to give the title compound (170 mg, 43%).
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.C(NCCNCC1C=CC=CC=1)C1C=CC=CC=1.[N+:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]CCCCCCCCCC)([O-:29])=[O:28].C=O>C1(C)C=CC=CC=1.CO>[N+:27]([CH2:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([O-:29])=[O:28]
Reactant: CCCCCCCCCCCCCCCCCC[N+](=O)[O-]
Agent: C=O
Agent: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CCc1ccccc1
Yield: 222.9 %

Procedure:
In a 500 mL round-bottom flask N,N′-dibenzylethylenediamine diacetate (4.78 g, 13 mmol) and 1-nitrooctadecane (3, 3.97 g, 13 mmol) are dissolved in 1:1 toluene/methanol (100 mL). Paraformaldehyde (1.39 g, 46.5 mmol) is added portionwise to the solution and the resulting suspension is refluxed. The mixture becomes homogeneous (dissolution of paraformaldehyde) and after 3 h at reflux, the mixture is cooled and evaporated in vacuo. The residue is recrystallized from ethanol, obtaining pure 4 (4.38 g, 61%) as colourless solid. M.p. 70-72° C. (EtOH), ESI-MS: 586 (MNa+), 564 (MH+); (Calc. for C36H57N3O2: 563 u.m.a.).
Reaction SMILES: C[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Li+].[OH-].Cl>CO.O>[OH:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:2][C:3]([OH:5])=[O:4])=[CH:8][CH:9]=1
Reactant: CC(Cc1ccc(CO)cc1)C(=O)O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
Intermediate B (5 g, 25.7 mmol) was dissolved in MeOH (50 mL) and water (10 mL). LiOH (1.85 g, 77.2 mmol) was added and the reaction stirred at RT for 18 h. The reaction mixture was acidified to pH ˜3 with 1M HCl, the resulting precipitate was isolated by filtration to afford the desired product (4.57 g, quant.). 1H NMR (300 MHz, d6-DMSO) δ: 7.18 (4H, q), 4.45 (2H, d), 2.81 (2H, t), 2.62 (2H, t).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: OB(O)c1ccccc1OC(F)(F)F
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2OC(F)(F)F)C1
Yield: 76.7 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 2-trifluoromethoxyphenylboronic acid (188 mg, 0.912 mmol) in ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (190 mg, 76.6%) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]1([CH2:27][O:28][C:29]2[N:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][O:28][C:29]2[N:34]=[CH:33][C:32]([C:2]3[CH:11]=[CH:10][C:9]4[N:8]=[CH:7][C:6]5[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]6[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=6)[C:5]=5[C:4]=4[CH:3]=3)=[CH:31][CH:30]=2)[CH2:25][CH2:26]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(OCC3CC3)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(OCC5CC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.107 mmol) and 6-(cyclopropylmethoxy)pyridine-3-boronic acid pinacol ester (ABCR, Karlsruhe, Germany, 36 mg, 0.131 mmol) to give the title compound as a white solid. (HPLC: tR 2.88 min (Method A); M+H=441 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.29-8.23 (m, 1H), 8.16-8.04 (m, 2H), 7.92-7.85 (m, 1H), 7.80-7.72 (m, 1H), 7.49-7.43 (m, 1H), 6.98-6.90 (m, 1H), 4.15-4.09 (m, 2H), 3.90 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H), 1.31-1.17 (m, 1H), 0.62-0.48 (m, 2H), 0.40-0.30 (m, 2H))
Reaction SMILES: C([O:5][C@@H:6]([CH3:35])[C@H:7]([NH:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:32][CH:31]=[CH:30][CH2:29]2)=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:10]=2[N:9]=1)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:11]2[NH:12][C:8]([C@@H:7]([NH:18][C:19](=[O:34])[C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:29][CH:30]=[CH:31][CH2:32]4)=[O:27])=[C:22]([CH3:33])[CH:21]=3)[C@@H:6]([OH:5])[CH3:35])=[N:9][C:10]=2[CH:16]=1
Reactant: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)[C@H](C)OC(C)(C)C)ccc1C(=O)N1CC=CC1
Agent: ClCl
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)N[C@H](c2nc3cc(Cl)ccc3[nH]2)[C@H](C)O)ccc1C(=O)N1CC=CC1
Yield: 99 %

Procedure:
Prepared analogously to Example 17 from N-[(1R,2S)-2-tert-butoxy-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbenzamide, and trifluoroacetic acid. Yield: 99%; Rf value: 0.48 (silica gel: dichloromethane/ethanol=9:1); C23H23ClN4O3 (438.913); mass spectrum: (M+H)+=439/441 (chlorine isotope) and (M−H)-=437/439 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[H-].[Na+].I[C:13]1[C:14](=[O:20])[NH:15][C:16]([CH3:19])=[CH:17][CH:18]=1>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:13]2[C:14](=[O:20])[NH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: Cc1ccc(I)c(=O)[nH]1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
4-Methoxythiophenol (1.7 mL, 13.85 mmol) was added to a suspension of NaH 60% in oil (831 mg, 20.80 mmol) in DMF (30 mL) at 0° C., and the mixture was allowed to warm to 25° C. 3-Iodo-6-methyl-1H-pyridin-2-one (3 g, 12.78 mmol) was added to the solution at 0° C., followed by CuI (533 mg, 2.8 mmol). The reaction was stirred at 25° C. for 1 h and heated at 120° C. for 5 h. Then it was allowed to cool and partitioned between CH2Cl2 (30 mL) and 9:1 NH4Cl/NH4OH (30 mL) and stirred for 15 min. The mixture was extracted with CH2Cl2 (3×70 mL each) and the combined CH2Cl2 extracts were washed with water (3×30 mL), brine, dried and stripped in vacuo to give the crude product (3.6 g), which was further purified by washing with ether to give 2.93 g of 3-(4-methoxyphenylsulfanyl)-6-methyl-1H-pyridin-2-one which was used in the next step.