Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:7]([OH:10])(=[O:9])[CH3:8].C(OO)(C)(C)C.[O-]O>>[C:7]([O:10][CH:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)(=[O:9])[CH3:8]
Reactant: C1=CCCCC1
Reactant: CC(=O)O
Agent: CC(C)(C)OO
Agent: [O-]O
Product: CC(=O)OC1C=CCCC1

Procedure:
In order to demonstrate that the 3,6-diacyloxycyclohexene can be prepared in a single step procedure, a mixture of 20.5 g. (0.25 moles) cyclohexene, 45 g. (0.75 moles) acetic acid and 45 g. of 90.5 weight percent purity tertiary butyl hydroperoxide (0.45 moles) and 0.4 g. cuprous chloride was heated at 80° - 85° C. for 10 hours at which time it was found that 97 weight percent of the hydroperoxide had been consumed. Analysis by glpc showed that 21 mole percent yield to 3-acetoxycyclohexene and a 25 mole percent yield to 3,6-diacetoxycyclohexene was obtained. The reaction mixture was treated as in Example I and the product distilled at 92° C. under 1 mm Hg pressure. Very little high boiling residue was found. It will be noted that although 0.5 moles of the hydroperoxide solution was used since it was not pure only 0.45 moles of the hydroperoxide itself was employed, i.e. slightly less than the desired 2:1 mole ratio of hydroperoxide to cyclohexene, a good yield of the diester was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[F:20][C:21]1[CH:46]=[CH:45][C:24]([C:25]([NH:27][C:28]2[S:29]C3C(N4CCOCC4)=CC=C(OC)C=3N=2)=[O:26])=[CH:23][CH:22]=1>>[CH2:9]([O:8][C:5]1[C:4]2[N:11]=[C:28]([NH:27][C:25](=[O:26])[C:24]3[CH:45]=[CH:46][C:21]([F:20])=[CH:22][CH:23]=3)[S:29][C:3]=2[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)[CH3:10]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reactant: C1CCNCC1
Reactant: CCOc1ccc(Br)cc1[N+](=O)[O-]
Product: CCOc1ccc(N2CCCCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-ethoxy-2-nitro-benzene and piperidine as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a yellow solid in 10% overall yield, MS: m/e=400 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[O:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1>>[O:30]1[CH:34]=[CH:33][C:32]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:12]=[CH:13][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]=2[CH3:29])=[CH:31]1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1ccoc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccoc1)OCC2c1ccc(C(C)C)cc1
Yield: 51 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and 3-furylboronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 51%. Melting point: 183-185° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8](=[CH:11][CH3:12])[CH2:7][CH:6]1[C:13]([O:15]C)=[O:14])=[O:4].[Mn]([O-])(=O)(=O)=[O:18].[K+].C[C:24]([CH3:26])=[O:25]>C(O)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][C:8]2([C:11]3([CH3:12])[O:18][CH2:26][CH2:24][O:25]3)[CH2:7][CH:6]1[C:13](=[O:14])[O:15]2)=[O:4]
Reactant: CC(C)=O
Reactant: CC=C1CCC(C(=O)OC)C(C(=O)OC)C1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)C1CCC2(C3(C)OCCO3)CC1C(=O)O2
Reaction time: 1 h
Yield: 33 %

Procedure:
8 g of 1,2-di-(methoxycarbonyl)-4-ethylidene-cyclohexane, prepared as described in Example 2, was dissolved in aqueous acetone containing 4.8 ml of acetic acid. An aqueous solution of potassium permanganate was added, and the mixture was allowed to stand for 60 minutes at room temperature. The excess oxidant was then destroyed and the reaction mixture, diluted with water, was extracted with ethyl acetate. The organic phase, washed with water and dried over anhydrous sodium sulphate, was evaporated to dryness under vacuum. The residue (9 g) was dissolved in benzene and refluxed for 60 minutes in the presence of a catalytic amount of p-toluenesulphonic acid. 4 ml of ethylene glycol was added and the reaction mixture was refluxed for a further 2 hours. After conventional work-up, the residue, obtained by evaporating off the solvent, was purified by chromatography on a column of silica gel using as eluent a toluene:acetone mixture (15:1 by volume). 3.0 g of the title compound was isolated (yield 33%): m.p. 69°-71° C.; m/z 271 (MH+.).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-]>CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Si:5]([O:8][CH:9]1[CH2:13][CH:12]2[CH:11]([CH:16]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10]1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:7])[CH3:6]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=CC1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)C1C2CC(O[Si](C)(C)C(C)(C)C)CC21
Reaction time: 8 h
Yield: 73 %

Procedure:
To a flask was added tert-butyl(cyclopent-3-en-1-yloxy)dimethylsilane (0.5 g, 2.52 mmol) and rhodium(II) acetate dimer (22 mg, 0.05 mmol). The flask was evacuated and purged 5 times with argon. Dichloromethane (8.4 mL) was added and the flask was evacuated and purged 5 times with argon. In a separate flask, ethyl diazoacetate (0.37 mL, 3.02 mmol) was added. The flask was evacuated and purged with argon five times. Dichloromethane (8.4 mL) was added and the solution was added to the first flask via syringe pump over a six hour time period and then allowed to stir overnight. The mixture was filtered over a pad of celite and then concentrated. Flash chromatography was used for purification to yield ethyl 3-{[tert-butyl(dimethyl)silyl]oxy}bicyclo[3.1.0]hexane-6-carboxylate (524 mg, 1.84 mmol, 73% yield). 1H NMR (500 MHz, CDCl3) δ 4.13-4.03 (m, 2H), 2.37-2.20 (m, 1H), 2.20-2.12 (m, 1H), 2.11-1.96 (m, 1H), 1.94-1.70 (m, 4H), 1.35-1.14 (m, 4H), 0.89-0.79 (m, 9H), 0.05-−0.11 (m, 6H).
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[CH2:24]([Li])[CH2:25][CH2:26][CH3:27].[CH3:29][C:30]1([C:35]2(C=O)[CH2:37][CH2:36]2)[O:34][CH2:33][CH2:32][O:31]1>C(OCC)C>[CH:24]([C:35]1([C:30]2([CH3:29])[O:34][CH2:33][CH2:32][O:31]2)[CH2:37][CH2:36]1)=[CH:25][CH2:26][CH3:27]
Reactant: CC1(C2(C=O)CC2)OCCO1
Reactant: [Li]CCCC
Agent: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: CCC=CC1(C2(C)OCCO2)CC1
Reaction time: 1 h

Procedure:
7.2 g of propyltriphenylphosphonium bromide is dissolved in 100 ml of diethyl ether, and 7.5 ml of n-butyllithium solution (2.5 M in hexane) is added in drops under nitrogen at room temperature. It is stirred for 1 hour, and then 2.34 g of aldehyde 7 is added to 10 ml of diethyl ether. It is stirred for 1 more hour, quenched with sodium chloride solution, extracted with ethyl acetate, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate/hexane, whereby 1.8 g of title substance 197 is obtained as a colorless oil (1:3 E,Z-mixture that cannot be separated).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][CH2:10][CH2:11][CH:12]=O)[CH3:3].[C:17]1([C:23]2[N:27]=[C:26]([NH2:28])[N:25](C)[N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:30]1(C)C=CC=CC=1>>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:28][C:26]1[NH:25][N:24]=[C:23]([CH2:17][C:22]2[CH:30]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:27]=1)[CH3:3]
Reactant: Cc1ccccc1
Reactant: CN(C)Cc1cccc(OCCCC=O)c1
Reactant: Cn1nc(-c2ccccc2)nc1N
Product: CN(C)Cc1cccc(OCCCCNc2nc(Cc3ccccc3)n[nH]2)c1
Reaction time: 2 h

Procedure:
A solution of 4-[3-[(dimethylamino)methyl]phenoxy]butanal (0.5 g) and 3-phenyl methyl-1H-1,2,4-triazole-5-amine (0.39 g) in dry toluene (60 ml) was heated under reflux during 3 h. The solvent was evaporated and replaced with methanol (50 ml). Sodium borohydride (0.4 g) was added and the mixture was stirred at 20° during 2 h. The methanol was evaporated and the residue partitioned between water and ethyl acetate. The organic extract was evaporated and the residue was purified by column chromatography to give the title compound, which crystallised from a mixture of ethyl acetate and cyclohexane as pale yellow crystals (0.09 g) m.p. 131°-3°; tlc system A,Rf 0.6.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:7](=O)[NH:8][C:4]=2[CH:3]=1.Cl[CH2:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].[C:43](=O)([O-])[O-:44].[K+].[K+]>CN(C)C=O>[CH2:33]([O:32][C:30]([C:29]1[CH:28]=[C:27]([CH:42]=[CH:41][CH:40]=1)[CH2:26][N:8]1[C:43](=[O:44])[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:14][CH2:15]2)[N:6]([C:5]2[CH:23]=[CH:24][CH:2]=[CH:3][CH:4]=2)[CH2:7]1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(OCc1ccccc1)c1cccc(CCl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCc3ccccc3)c1)CN2c1ccccc1
Temperature: 65 °C
Yield: 85.4 %

Procedure:
A mixture of tert-butyl 4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (637 mg, 1.923 mmol, 1 equiv), benzyl 3-(chloromethyl)benzoate (500 mg, 1.923 mmol, 1 equiv) and potassium carbonate (797.3 mg, 5.769 mmol, 3 equiv) in N,N-dimethylformamide was heated at 65° C. for 16 h. The reaction was partitioned between ethyl acetate and water. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified using the Biotage flash chromatography system (SNAP, 50 g cartridge, Rf=0.4, gradient—5%-30% ethyl acetate in hexanes) to afford the tert-butyl 3-(3-(benzyloxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate as an oil (913 mg, 85.6%). MS for C33H37N3O5 m/z 556.27 (M+H)+.
Reaction SMILES: FC1C(O[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=[O:10])=C(F)C(F)=C(F)C=1F.[NH2:37][CH2:38][C:39]1[O:40][CH:41]=[CH:42][CH:43]=1>O>[O:40]1[CH:41]=[CH:42][CH:43]=[C:39]1[CH2:38][NH:37][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[N:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=1)=[O:10]
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: NCc1ccco1
Solvent: O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4ccco4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3-[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and 2-aminomethylfuran according to Procedure K: mp>250° C.; 1H NMR (DMSO-d6): δ 4.51 (d, J=5.5 Hz, 2H), 6.31 (d, J=3 Hz, 1H), 6.44 (d, J=3 Hz), 702 (d, J=8.3, 1H), 7.30 (s, 2H), 7.66 (m, 3H), 7.88 (m, 3H), 8.18 (s, 1H), 9.02 (br t, J=5.5 Hz, 1H), 11.4 (s, 1H), 12.8 (s, 1H); APCI−MS m/z 438 (M−H)−; Anal. Calcd for C20H17N5O5S.1/2 H2O: C, 53.57; H, 4.05; N, 15.62; S, 7.15. Found: C, 53.91; H, 4.01; N, 15.13; S, 6.78.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:18]([OH:20])=O.[NH2:26][C:27]1[CH:28]=[C:29]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:44])[CH3:43])[CH:37]=2)[CH:30]=[CH:31][C:32]=1[F:33].CN(C=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:43][N:42]([CH3:44])[C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[C:35]([NH:34][C:29]1[CH:30]=[CH:31][C:32]([F:33])=[C:27]([NH:26][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH3:13])[CH:16]=2)[CH:28]=1)=[O:45]
Reactant: CN(C)c1cccc(C(=O)Nc2ccc(F)c(N)c2)c1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)ccc2F)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) in methylene chloride (5 ml) was added to a stirred mixture of 3,4-dimethoxybenzoic acid (0.91 g), N-(3-amino-4-fluorophenyl)-3-dimethylaminobenzamide (0.14 g), DMF (2 ml) and 4-dimethylaminopyridine (0.004 g). The reaction mixture was stirred at ambient temperature for 18 hours. Water (20 ml) and methylene chloride (10 ml) were added. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 49:1 mixture of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound (0.084 g) as a colourles solid, m.p. 187-188° C.; NMR Spectrum: (CDCl3) 3.02 (s, 6H), 3.97 (s, 6H), 6.86 (m, 1H), 6.93 (d, 1H), 7.09 (d, 1H), 7.16 (t, 1H), 7.25 (m, 1H), 7.32 (t, 1H), 7.41 (m, 1 H), 7.5 (d, 1H), 7.88 (m, 1H), 7.97 (s, 1H), 8.04 (s, 1H), 8.42 (m, 1H);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([O:27]CC)=[O:26])=[CH:9]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[CH:16]=3)[C:11](=[O:24])[C:10]([C:25]([OH:27])=[O:26])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Yield: 100.1 %

Procedure:
A mixture of 2.8 g of ethyl 1-(4-fluorophenyl)1,4 -dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylate, 20 ml of 10% potassium hydroxide solution and 10 ml ethanol was heated on a steam bath for 3 hrs. The reaction mixture was cooled and acidified with acetic acid. The solid product was collected and washed with acetone to give 2.6 g 1-(4-fluorophenyl)-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylic acid. A sample of the compound was converted to its monomethanesulfonate salt, m.p. 280-281° C. when recrystallized from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5]([OH:7])=O.C1N=CN(C([N:33]2[CH:37]=[N:36]C=C2)=O)C=1.[C:38]([O:41][CH2:42][CH3:43])(=[O:40])C>>[CH2:42]([O:41][C:38]([C:37]1[N:36]=[C:5]([C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:14])([F:15])[F:16])=[C:2]([Cl:1])[CH:3]=2)[O:7][N:33]=1)=[O:40])[CH3:43]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCOC(C)=O
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: CCOC(=O)c1noc(-c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, 150 mg, 0.238 mmol) in ethyl acetate (5 mL) at 0° C. was added CDI (68 mg, 0.42 mmol). The mixture was stirred for 30 min. at 0° C. Additional ethyl-2-oxoiminooxamate (55 mg, 0.42 mmol) was added. The reaction mixture was washed with water, sat aq NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The residue yellow waxy solid was dissolved in N,N-dimethylformamid (2 mL) and stirred for 3 h at 90° C. and 2 h at 140° C. The mixture was cooled to room temperature, poured in water (20 mL) and extracted twice with AcOEt. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, heptane/AcOEt 3:1) to give title compound (113 mg) as a white waxy solid. MS (m/e)=490.0 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[CH3:12][O:13][NH:14][CH3:15].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:13][CH3:12])[CH3:15])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: CNOC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccccc1Cl
Reaction time: 8 h

Procedure:
50 ml of 2-chlorobenzoyl chloride are added slowly to a mixture of 37.33 g of N-methoxymethanamine hydrochloride and 104 ml of triethylamine in 500 ml of DCM and the mixture is left to stir overnight at AT. Water is added to the reaction mixture, the mixture is extracted with DCM, the organic phase is washed with a buffer solution pH=2 and dried over Na2SO4, and the solvent is evaporated off under vacuum. 78.57 g of the expected compound are obtained.
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].Cl[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[N:9][CH:10]=1
Reactant: CCS(N)(=O)=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 130 °C
Yield: 72 %

Procedure:
20.3 g of ethanesulfonamide and 26.0 g of 2-chloro-5-trifluoromethylpyridine were dissolved in 220 ml of dimethylsulfoxide, and 47.4 g of anhydrous potassium carbonate was further added thereto. This solution mixture was heated to 130° C. and reacted for 5 hours. After completion of the reaction, the reaction product was poured into 1 l of water. Undissolved materials in water were extracted with ethyl ether and removed. Then, the aqueous layer was adjusted to pH4 with concentrated hydrochloric acid, and precipitated crystals were collected by filtration and dried to obtain 26.2 g of N-(5-trifluoromethyl-2-pyridyl)ethanesulfonamide having a melting point of from 164° to 165° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CO.[Br:15]Br>C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([C:9]([Br:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1C
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1c(Br)ccc(N)c1C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a mixture of methyl 3-amino-2-methylbenzoate (5.00 mL, 34.7 mmol) in acetic acid (100 mL)-methanol (200 mL) was added bromine (5.55 g, 34.7 mmol) under ice-cooling, and the mixture was stirred for 5 min. The reaction solution was diluted with saturated aqueous sodium thiosulfate solution, and the organic solvent was evaporated under reduced pressure. The residual aqueous solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=5/95→20/80) to give the title compound (4.66 g, yield 55%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:39]3[CH:38]=[CH:37][C:36]([N:33]4[CH2:32][CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:35][CH2:34]4)=[CH:41][CH:40]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C

Procedure:
2.64 (192 mg, 0.581 mmol), (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (355 mg, 1.16 mmol), K3PO4 (400 mg, 1.9 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (21 mg, 0.029 mmol) were taken up in 1,4-dioxane (10 mL) and water (1 mL). The stirred reaction mixture was heated to 100° C. for 1.5 h and was then cooled and partitioned between EtOAc (30 mL), water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-12.5% MeOH in DCM) to provide tert-butyl 4-(4-(3-(difluoromethyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C28H35F2N6O4: 557.3; found: 557.1.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH:3]([CH2:31][CH3:32])[CH:4]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([O:24]C)=[O:23])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][N:2]([CH3:33])[CH:3]([CH2:31][CH3:32])[CH:4]([C:10]1[CH:30]=[CH:29][C:13]2[N:14]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=3)[C:22]([OH:24])=[O:23])[S:16][C:12]=2[CH:11]=1)[N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: CCC(C(c1ccc2nc(NCc3cccc(C(=O)OC)c3)sc2c1)n1ccnc1)N(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C(c1ccc2nc(NCc3cccc(C(=O)O)c3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C

Procedure:
A solution of methyl 3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]-thiazol-2-yl)amino)methyl)benzoate (18 mg, 0.037 mmol) in 500 μL THF was treated with LiOH (10 mg, 0.238 mmol, 6.5 equiv) in 500 μL water. This was heated at 50° C. overnight. Afterwards the reaction was neutralized with 240 μL of 1N HCl and concentrated in vacuo. The residue was purified by prep-TLC using a 1 mm silica, plate eluting twice with 20% MeOH/DCM to provide 3-(((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)methyl)benzoic acid. MS ESI: m/z 462.21 [M−1+].