Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:24])[CH2:18][O:19][CH2:20][C:21](O)=[O:22])=[C:12]([C:25]([O:27]C)=[O:26])[CH:11]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:21](=[O:22])[CH2:20][O:19][CH2:18][C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][C:12]=2[C:25]([OH:27])=[O:26])=[O:24])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(Br)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1

Procedure:
Using the same method as in Example 1-(ii), 3-bromoaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester (yield: 81%)
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:40]1[CH:41]=[C:42]2[C:59](=[N:60][CH:61]=1)[NH:58][C:57](=[O:62])[C:44]1([CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1)[CH2:43]2>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:6]([O:5][C:1](=[O:4])/[CH:2]=[CH:3]/[C:40]1[CH:41]=[C:42]2[C:59](=[N:60][CH:61]=1)[NH:58][C:57](=[O:62])[C:44]1([CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:55])[CH3:56])=[O:51])[CH2:46][CH2:45]1)[CH2:43]2)[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Cc1cc(Br)cnc1NC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2

Procedure:
Ethyl acrylate (2.3 mL, 21.2 mmol), diisopropylethylamine (3.7 mL, 21.2 mmol) and P(o-tolyl)3 (323 mg, 1.06 mmol) were successively added to a suspension of tert-butyl 6-bromo-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (2.10 g, 5.3 mmol) in propionitrile (20 mL) and dimethylformamide (5 mL) in a sealed tube. The resulting mixture was then purged with argon prior to the addition of palladium acetate (120 mg, 0.53 mmol). The mixture was purged with argon again and refluxed overnight. The reaction mixture was then filtered on Celite®. The filtrate was concentrated to dryness and the residue was solubilized in dichloromethane (100 mL). The resulting solution was washed with a saturated solution of ammonium chloride (100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was precipitated in dichloromethane/diethylether/pentane, the title product was obtained as an off-white solid (1.52 g, 70%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.O.NN>C(O)C.[Ni].O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCNc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CN1CCN(CCCNc2ccc(N)cc2)CC1
Temperature: 50 °C

Procedure:
A suspension of 0.1385 gms. of [3-(4-methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine in 3 mL of ethanol is heated to 50° C. Once dissolution is achieved 0.144 mL hydrazine monohydrate is added to the solution. A Raney nickel slurry in water is added to the 50° C. solution dropwise, waiting after each addition for the gas evolution to cease. Sufficient quantities of Raney nickel have been added when continued addition of Raney nickel causes no further gas evolution. The reaction is then maintained at 50° C. for an additional hour, and subsequently is cooled to room temperature. The reaction mixture is filtered through a pad of celite (rinsing the pad with methanol). N-[3-(4-Methyl-piperazin-1-yl)-propyl]-benzene-1,4-diamine (0.116 gms.) is isolated upon evaporation of the filtrate, and is subsequently used without purification in the reaction of Example 302.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](/[C:10](/[C:17]2[CH:18]=[CH:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=2)=[CH:11]/[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:9])=[N:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOCC>[NH2:23][C:20]1[N:21]=[CH:22][C:17](/[C:10](=[CH:11]\[CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)/[C:8]([NH:7][C:5]2[S:6][C:2]([Cl:1])=[CH:3][N:4]=2)=[O:9])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Reaction time: 2 h

Procedure:
A stirred solution of (E)-tert-butyl {5-[1-(5-chlorothiazol-2-ylcarbamoyl)-2-cyclopentylvinyl]pyridin-2-yl}carbamate (Preparation 18, 212 mg, 473 μmol) in CH2Cl2 (5 mL) was treated with TFA (5 mL, 65.1 mmol). After 2 h, the mixture was evaporated to dryness, then EtOAc (60 mL) was added. The EtOAc solution was washed with H2O-saturated aqueous NaHCO3 (1:1, 20 mL) and brine (20 mL), before being dried (MgSO4). Filtration and solvent evaporation gave a residue that was dissolved in a minimal amount of Et2O. IH was added to the Et2O solution to precipitate a solid, which was collected and dried to furnish the title compound: RTA=3.07 min; m/z (ES+)=349.2 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])#[N:2]>[Pd].CO>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: [Pd]
Solvent: CO
Product: NCc1cccc(C(=O)O)c1

Procedure:
N-Boc-(3RS)-Aminomethylcyclohexanecarboxylic acid was prepared from commercially available 3-cyanobenzoic acid by catalytic hydrogenation using palladium on charcoal in methanol to give the 3-aminomethylbenzoic acid. This was reacted with Boc-ON, followed by hydrogenation with rhodium on aluminum oxide in methanol to yield N-Boc-(3RS)-aminomethylcyclohexane carboxylic acid. FAB+MS: (M+H)+ =258 This compound was then incorporated into the peptide using the methods described in Example 1 and isolated by the method described in Example 2. The diastereomers were separated by RP-HPLC.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][CH2:15][N:14](O)[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Ni]>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H]1CCN(O)C1)OCc1ccccc1
Agent: [Ni]
Solvent: CCO
Product: O=C(N[C@@H]1CCNC1)OCc1ccccc1
Yield: 81 %

Procedure:
The crude (R)-3-(benzyloxycarbonylamino)-N-hydroxy-pyrrolidine obtained above (1.4 g) was dissolved in ethanol (10 ml). Raney nickel (about 2 g) was added to this mixture. The reaction was degassed under reduced pressure and hydrogen supply (three times) and subsequently put under hydrogen atmosphere (1 bar). The reaction was over after 6 hours, yielding crude (R)-3-(benzyloxycarbonylamino)-pyrrolidine which was further processed in situ, in that di-tert-butyl dicarbonate (1.0 g, 4.58 mmol) was added; the mixture was stirred for one hour. The solvent was removed and the residue taken up in an n-hexane/AcOEt mixture (1:1, 20 ml) and filtered through a silicagel pad. The silica was washed with n-hexane/AcOEt mixture (1:1; 250 ml). The organic phases were evaporated. The compound was obtained as a colorless oil (1.125 g; yield 81%) in good purity, i.e. at least 90-95%, rendering the compound sufficiently pure for further reaction, e.g. in Example 3.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[CH2:15][CH2:14][CH:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH2:12]1.CN1CCOCC1.[CH3:32][N:33]([CH3:51])[C:34]1([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41](O)=[O:42])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>CN(C)C=O.O>[CH3:51][N:33]([CH3:32])[C:34]1([C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)[CH2:39][CH2:38][C:37](=[CH:40][C:41]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH2:12]2)=[O:42])[CH2:36][CH2:35]1
Reactant: c1ccc2c(C3CCNC3)c[nH]c2c1
Reactant: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1(c2ccc(F)cc2)CCC(=CC(=O)N2CCC(c3c[nH]c4ccccc34)C2)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 52 %

Procedure:
1-hydroxybenzotriazole (1.08 mg, 8 mmole), 3-pyrrolidine-3-yl-1H-indole (744 mg, 4 mmole) and N-methylmorpholine (0.888 ml, 8 mmole) were added in succession under argon to a solution of [4-dimethylamino-4-(4-fluorophenyl)-cyclohexylidene)-acetic acid (1.055 g, 4 mmole) in dry dimethylformamide (40 ml). The clear solution was cooled in an ice bath and dicyclohexylcarbodiimide (1.65 g, 8 mmole) was added. The reaction mixture was stirred for 5 days at room temperature, the dicyclohexylurea precipitating out little by little. The reaction mixture was worked up by separating the precipitated urea and adding the filtrate to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Further urea thereupon precipitated out, which was separated. The filtrate was diluted with water (300 ml) and 5M sodium hydroxide (7 ml, 35 mmole) was added. The crude product of 2-(4-dimethylamino-4-(4-fluorophenyl)cyclohexylidene)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone thereupon precipitated out as a beige-coloured solid (1.67 g). The chromatographic separation on silica gel (80 g) was carried out with EE/methanol (1:1). 2-(4-dimethylamino-4-(4-fluorophenyl)cyclohexylidene)-1-[3-(1H-indol-3-yl)pyrrolidine-1-yl]-ethanone was thereby obtained as a diastereoisomer mixture in a yield of 52% (916 mg) in the form of a colourless solid with a melting point of 109°-112° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][C@H:20]([OH:21])[CH2:22][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]
Reactant: CCNCC
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Solvent: C1CCOC1
Product: CCN(CC)C[C@@H](O)COc1cc2nccc(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)c2cc1C#N
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After adding tetrahydrofuran (4 ml) and diethylamine (0.2 ml) to N-(4-{6-cyano-7-[(2R)-oxiran-2-yl]methoxyquinolin-4-yloxy}-2-fluorophenyl)-N′-(thiazol-2-yl)urea (200 mg), the mixture was stirred at 50° C. for 2 hours. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (60 mg) as light yellow crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][N:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=4)[CH2:13]3)[C:9]2=[O:28])=[C:4]([CH3:29])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:29][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][CH2:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=3)[CH2:13]2)[C:9]1=[O:28])[C:36]#[N:37]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccc1N1CCC2(CCCN(c3ccc(C(F)(F)F)cn3)C2)C1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [C-]#N
Product: Cc1cc(C#N)ccc1N1CCC2(CCCN(c3ccc(C(F)(F)F)cn3)C2)C1=O
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(4-bromo-2-methylphenyl)-7-[5-(trifluoromethyl)pyridin-2-yl]-2,7-diazaspiro[4.5]decan-1-one (63.6 mg, 0.000136 mol), zinc cyanide (32 mg, 0.00027 mol), potassium carbonate (0.056 g, 0.00041 mol) and tetrakis(triphenylphosphine) palladium(0) (8 mg, 0.000007 mol) in N,N-dimethylformamide (0.5 mL, 0.006 mol) was stirred at 100° C. for 2 days. The reaction mixture was cooled to ambient temperature and purified by prep-HPLC (under pH 10) to afford the desired product. LC-MS: 415.2 (M+H)+.
Reaction SMILES: [C:1]([S:5]([CH2:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]([O:12]CC)=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+]>CS(C)=O.[OH-].[Ca+2].[OH-]>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]([OH:12])=[O:11])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: [Ca+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Yield: 48 %

Procedure:
A solution of 79 g (0.25 mol) of ethyl (RS)-α-[(tert-butylsulfonyl)methyl]hydrocinnamate in 105 ml of dimethyl sulfoxide was added dropwise while stirring vigorously to 6.2 l of water at 30° C. The pH value was adjusted to 7.5 with 0.1N sodium hydroxide solution. The hydrolysis was started by the addition of 1.05 g of α-chymotrypsin. The pH value was held constant at 7.5 using automatic titration by dosing-in 0.043N calcium hydroxide solution of 30° C. After a consumption of 2.67 l of 0.043N calcium hydroxide solution (after 19.5 hours), the reaction mixture was extracted three times with 2 l of ethyl acetate. The aqueous phase was acidified to pH 2.5 with 5% hydrochloric acid and extracted twice with 2 l of ethyl acetate. The organic phases were filtered over DICALITE Speedex, combined and dried over magnesium sulfate. After evaporating the solvent and drying the residue in a high vacuum, there were obtained 35 g (0.12 mol, 48.3%, 96.9% of theory) of (S)-α-[(tert-butylsulfonyl)methyl]hydrocinnamic acid in the form of white crystals, which had an enantiomeric excess of >98%. In order to determine the purity by gas chromatography, the compound obtained was silylated and had a purity of >99%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12](=[S:14])[NH2:13])[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3].Br[CH2:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:11]([C:12]2[S:14][CH:30]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[N:10]=[C:9]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Product: CCOC(=O)c1csc(N2N=C(c3cc(F)ccc3F)SC2(CCCN=[N+]=[N-])c2ccccc2)n1

Procedure:
Prepared from 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide as in Example 21, Step C, utilizing ethyl 3-bromo-2-oxopropanoate in place of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate, 57%.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[F:12][C:11]([F:13])([F:14])[C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1N
Temperature: 0 °C
Yield: 96.9 %

Procedure:
A solution of 2-nitro-4-trifluoromethylaniline (5.000 g, 24.26 mmol, Aldrich, used as received) and SnCl2.2 H2O (20.00 g, 88.64 mmol, Aldrich, used as received) in absolute ethanol (50 mL) was refluxed for 45 min. It was then poured into ice (85 g) and basified with 10% aq. NaHCO3 (250 mL). The resulting suspension was extracted with ethyl acetate (400 mL). The ethyl acetate extract was dried over Na2SO4 and evaporated to give 4.14 g (87%) of pure 4-trifluoromethyl-1,2-phenylenediamine as a red powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.O.C(OCC)(=O)C>CN(C)C=O.C(N(C(C)C)CC)(C)C>[F:10][C:9]([F:12])([F:11])[C:5]1[C:6]([Cl:8])=[CH:7][C:2]([NH:16][CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
1,5-Dichloro-2-nitro-4-(trifluoromethyl)benzene (5.5 g) was dissolved in dry dimethylformamide (50 ml) and diisopropylethylamine (5.1 ml), and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (5.0 g) were added at room temperature. The mixture was stirred at 80° C. for 2.5 h, then water and ethyl acetate added. The organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated, and the residue was crystallised from diethyl ether to afford the subtitle compound, 6.7 g.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][N:21]2[CH:24]=[CH:25][N:26]=[C:20]2[CH:19]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>ClCCl.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.CC([O-])=O.CC([O-])=O.[Pd+2].O>[Br:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:24]1[N:21]3[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH2:15][O:14][CH3:13])=[CH:19][C:20]3=[N:26][CH:25]=1)[CH:11]=[CH:10]2
Reactant: Brc1ccc2cccc(Br)c2n1
Reactant: COCCOc1ccn2ccnc2c1
Agent: [Pd+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COCCOc1ccn2c(-c3ccc4cccc(Br)c4n3)cnc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of 2,8-dibromoquinoline (22.4 g, 78.0 mmol), 7-(2-methoxyethoxy)imidazo[1,2-a]pyridine (15.0 g, 78.0 mmol), Pd(PPh3)4 (4.51 g, 3.90 mmol), K2CO3 (21.6 g, 156 mmol) and Pd(OAc)2 (0.876 g, 3.90 mmol), dioxane (312 mL) and water (3 ml) was heated to 100° C. for 18 hours. The resulting mixture was diluted with dichloromethane (500 ml) and filtered. The filtrate was concentrated under reduced pressure and to the resulting oil was added ethyl acetate (100 ml) and methyl tert-butyl ether (100 ml). The resulting mixture was stirred overnight. Filtration to collect the resulting solids yielded the title compound (22.2 g, 72% yield). MS ESI (+) m/z 398 and 400 (M+1 of each isotope) detected.
Reaction SMILES: [OH:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4].Cl[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C(Cl)Cl>[CH:16]([S:17]([O:1][N:2]1[C:11](=[O:12])[CH:10]2[CH:5]([CH:6]3[CH2:13][CH:9]2[CH:8]=[CH:7]3)[C:3]1=[O:4])(=[O:19])=[O:18])=[CH2:15]
Reactant: O=S(=O)(Cl)CCCl
Reactant: O=C1C2C3C=CC(C3)C2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)ON1C(=O)C2C3C=CC(C3)C2C1=O
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A suspension of 5.38 g (30.0 mmol) of N-hydroxy-5-norbornene-2,3-dicarboximide and CH2Cl2 (120 ml) is successively treated with 2-chloroethanesulfonyl chloride (6.3 ml, 60.0 mmol) at room temperature and triethylamine (12.5 ml, 90.0 mmol) at 0° C. Stirring is continued for 1.5 h at room temperature and the resulting reaction mixture is treated with 10% aqueous sodium carbonate solution (100 ml) and ethyl acetate (200 ml). The organic phase is washed with. water (100 ml), dried over Na2SO4, and concentrated. The residue is further dried under vacuum, providing 5.89 g of pure product as light-yellow solid. The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 1.53 (d, 1H), 1.76-1.81 (m, 1H), 3.12 (s, 2H), 3.48 (s, 2H), 6.17 (s, 2H), 6.29 (d, 1H), 6.53 (d, 1H), 6.78 (dd, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[N:12]=[CH:13][N:14]([CH3:16])[CH3:15])#[N:2].[OH-].[Na+].[Cl-].[Na+]>O1CCCC1.Cl.O.C(OCC)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([N:12]=[CH:13][N:14]([CH3:15])[CH3:16])[CH:5]=1
Reactant: CN(C)C=Nc1cc([N+](=O)[O-])ccc1C#N
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C=Nc1cc(N)ccc1C#N
Temperature: 0 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
N′-(2-Cyano-5-nitrophenyl)-N,N-dimethylformimidamide (1.0 g, 4.58 mmol) is dissolved in 100 mL of tetrahydrofuran, cooled to 0° C. and admixed with titanium trichloride solution (69 mL of a 15% solution in 10% aqueous HCl). Then, the batch is stirred at room temperature for 4 hours and adjusted at 0° C. to pH 9 with 2N aqueous sodium hydroxide solution. The mixture is diluted with water and ethyl acetate. The aqueous phase is saturated with sodium chloride and stirred out three times with ethyl acetate. The combined organic phases are dried over sodium sulphate. Removal of the solvent and also chromatographic purification (silica gel, n-hexane/ethyl acetate:→100% ethyl acetate) gives the desired product in 73% yield (630 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
o-Anisidine (2.34 ml, 20 mmol) was dissolved in toluene (60 ml) to which were subsequently added, with cooling in an ice bath, pyridine (4.58 ml, 60 mmol), p-toluenesulfonyl chloride (3.89 g, 20 mmol) and a catalytically effective amount of 4-dimethylaminopyridine. After 2.5 hours of stirring at room temperature, the resulting reaction solution was mixed-with water (50 ml), extracted with ethyl acetate and then washed with water, 10% sodium hydroxide aqueous solution, 1N hydrochloric acid, water and saturated brine in that order. After drying on anhydrous magnesium sulfate and removing the solvent by evaporation, the resulting orange solid was dissolved in ethyl acetate (50 ml), adsorbed to anhydrous magnesium sulfate (20 g), eluted with ether and then subjected to evaporation to remove the solvent. The resulting colorless solid which was then washed with an ether-hexane (1:1) mixture solution to obtain 3.44 g (62.0%) of the title compound in the form of colorless prism crystals.