Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[S:25][CH2:24][CH2:23][NH:22][C:21](=O)[CH2:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>C(OCC)C.O1CCCC1.O>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[S:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(C2CC(=O)NCCS2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2CCNCCS2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 57.7 %

Procedure:
Lithium aluminum hydride (190 mL of a 1M ethereal solution) is cooled to 0° C. and treated with aluminum chloride (8.44 g, 63.2 mmol) in 15 mL of diethyl ether. The resulting clear solution is stirred at 0° C. for 20 minutes and then a slurry of tetrahydro-7-(4-methoxyphenyl)-1,4-thiazepin 5-one (15.0 g, 63.2 mmol) in 150 mL of tetrahydrofuran is added. The reaction is then allowed to warm to room temperature for 12 hours and is treated with 14.4 mL of water, 7.2 mL of a 10% aqueous sodium hydroxide solution and 36 mL of water. The mixture is stirred for 3 hours and filtered. The filtrate is concentrated to obtain 8.14 g of a clear oil. The oil is converted to the hydrochloride salt; mp 209°-212° C.
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](O)=[O:6].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:5](=[O:6])[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:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)=[CH:31][CH:30]=1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42.7 %

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 (80 mg, 0.2 mmol) and 4-amino-benzoic acid methylester (34 mg, 0.22 mmol) in N,N-dimethylformamide (4 ml) were added 4-methylmorpholine (62 mg, 0.61 mmol) and HBTU (115 mg, 0.3 mmol). The mixture was stirred for 17 h at room temperature. The reaction solution was poured in water, extracted twice with AcOEt, washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (5 g silica gel, heptane/AcOEt 4:1) to give the title compound (45 mg) as a white solid. MS (m/e)=527.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]([F:34])=[C:31]([F:33])[F:32].Cl>O>[Cl:1][C:2]1[C:7]([O:8][C:31]([F:33])([F:32])[CH:30]([Cl:29])[F:34])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: FC(F)=C(F)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC(F)(F)C(F)Cl)c(Cl)cc2F)c1=O
Reaction time: 0.17 h

Procedure:
A solution of 2.0 g of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-methyl-6 -trifluoromethyl-2,4(1H,3H)pyrimidinedione is treated with 0.25 g of potassium carbonate and the suspension is saturated with chlorotrifluoroethylene while stirring during 10 minutes. The reaction mixture is subsequently heated to 50° C. for 10 minutes, during which a slow stream of chlorotrifluoroethylene is conducted in. Thereafter, the reaction mixture is poured into a solution of 3 ml of 2N hydrochloric acid in 250 ml of water, and the whole is extracted with 100 ml of ethyl acetate. The organic phase is washed neutral with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is purified by chromatography on a silica gel column using diethyl ether/n-hexane (1:3) as the eluent. There is obtained 3-[4-chloro-5-(2-chloro-1,1,2-trifluoroethoxy)-2-fluorophenyl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 1H-NMR (CDCl3, 400 MHz : 7.40 ppm (d,1H), 7.32 ppm (m,1H), 6.37 ppm (s,1H), 6.33 ppm (m,1H), 3.57 ppm (d,3H).
Reaction SMILES: F[C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)=S>CC(C)=O>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:7]3[CH:2]=[C:3]([NH2:18])[C:4]([NH2:15])=[CH:5][CH:6]=3)[CH2:9][CH2:10]2)[CH2:4][CH2:3][CH2:2][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: O=C([O-])[O-]
Agent: S=C(Cl)Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: Nc1ccc(N2CCN(C3CCCC3)CC2)cc1N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1 (1 eq) and sodium carbonate (1.5 eq) in acetone was stirred in an ice bath under an atmosphere of nitrogen. Thiophosgene (1.5 eq) was added drop wise over 30 minutes. The reaction was stirred for another 30 minutes in the ice bath before being removed and allowed to warm to RT. The reaction was stirred at RT for 1.5 h before the reaction solution was concentrated under vacuum. Toluene was added to the crude product and removed under vacuum to azetrope off any residual thiophosgene and afford the product 2. MS: MH+=219
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].[Cl:9]N1C(=O)CCC1=O>C1COCC1.O>[Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1ccsc1Br
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(Cl)sc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-bromo-3-hydroxymethylthiophene from Example 1, Step 1 (13.0 g, 67.3 mmol) in THF (100 mL) and water (10 mL) was added N-chlorosuccinimide (9.88 g, 74.0 mmol) and the mixture was stirred at r.t. for 5 h and concentrated in vacuo. The residue was worked up as above to afford the desired product. The crude product was used directly.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C.[F:25][C:26]1[CH:27]=[C:28]([S:33](Cl)(=O)=O)[CH:29]=[CH:30][C:31]=1[F:32].Cl>C(Cl)Cl>[F:25][C:26]1[CH:27]=[C:28]([SH:33])[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1ccc(S)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of triphenylphosphine (37.0 g) and DMF (2 ml) in DCM (100 ml) was maintained at 20° C. with an ice bath during addition of 3,4-difluorobenzenesulphonyl chloride (10 g). The mixture was stirred at room temperature for 2 hours then aqueous hydrochloric acid (50 ml of a 1M solution) was added. The mixture was stirred for a further 1 hour. The organic layer was separated, dried and the solvent removed by evaporation to give the title compound as an oil which was used without purification.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20](N)=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.NC1C=C(C(C2C=CC=C(N)C=2)(C(F)(F)F)C(F)(F)F)C=CC=1.OC1C=CC(C(C2C=CC(O)=CC=2)(C(F)(F)F)C(F)(F)F)=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.FC(F)(F)S(O)(=O)=O>[Pd].C(N(CC)CC)C>[C:17]1([C:8]([C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(c2ccc(N)cc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Pd]
Agent: Nc1cccc(C(c2cccc(N)c2)(C(F)(F)F)C(F)(F)F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: FC(F)(F)C(c1ccccc1)(c1ccccc1)C(F)(F)F

Procedure:
On the other hand, a process is described in the literature (K. S. Y. Lau et al., Journal of Polymer Science, Polymer Chemistry Edition, 20. 2381-2393 (1982)) which facilitates the preparation of an isomeric diamine to 2,2-bis-(4-aminophenyl) hexafluoropropane from, 2,2-bis-(3-aminophenyl)hexafluoropropane, in very high yields. For this, the process also starts out from 2,2-bis-(4-hydroxyphenyl)hexafluoropropane, the hydroxyl groups of which are converted into F3C-SO3 groups by reaction with trifluoromethanesulfonic anhydride. Trifluoromethanesulfonic acid is eliminated from this compound in a second step by catalytic hydrogenation with a palladium/charcoal catalyst which is suspended in triethylamine and 2,2-bisphenylhexafluoropropane is thus obtained. This compound is nitrated using nitric acid in concentrated sulfuric acid to give 2,2-bis-(3-nitrophenyl)hexafluoropropane in a third step which is then hydrogenated on a palladium/charcoal catalyst to give 2,2-bis-(3-aminophenyl)hexafluoropropane in a fourth step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[OH:9].O[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([O:9][C:3]2[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: Oc1cc(I)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(I)ccc2Cl)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 79.7 %

Procedure:
2-Chloro-5-iodophenol (2.50 g, 9.83 mmol), tert-butyl 4-hydroxy-1-piperidinecarboxylate (2.97 g, 14.7 mmol) and triphenylphosphine (5.15 g, 19.6 mmol), were suspended in THF (50 mL) and cooled to 0° C. Diethyl azodicarboxylate (3.08 mL, 19.6 mmol) was then added dropwise, the reaction was stirred under a N2 atmosphere for 18 h. The reaction was then partitioned between H2O and EtOAc. The organic layer was separated, washed with saturated brine, dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 0-50% EtOAc/cyclohexane, to afford the title compound (3.43 g, 80%). (Method 3): Rt 4.98 min, m/z 337.9 [M−BOC+].
Reaction SMILES: ClC1C=CC(C(N)C(N)CC)=CC=1.Cl.C(OC1C=C(OC)C=CC=1C(=N)OCC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[NH:42][C:41]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=3[O:51][CH2:52][CH3:53])=[N:40][CH:39]2[CH2:54][CH:55]2CCCC2)=[CH:34][CH:33]=1>>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([CH:38]2[NH:42][C:41]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][C:44]=3[O:51][CH2:52][CH3:53])=[N:40][CH:39]2[CH2:54][CH3:55])=[CH:36][CH:37]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: CCC(N)C(N)c1ccc(Cl)cc1
Agent: CCOC(=N)c1ccc(OC)cc1OCC
Agent: Cl
Product: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1

Procedure:
5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-butane-1,2-diamine and ethyl 2-ethoxy-4-methoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 359.1524, calculated for C20H24N2O2Cl [(M+H)+]359.1521.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:9]=[C:10]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[N:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([O:19][C:17]([C:10]1[N:11]2[C:16]([CH:15]=[CH:14][CH:13]=[CH:12]2)=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=1)=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)c1cc(C(=O)OCc2ccccc2)n2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc(C(=O)OCc2ccccc2)n2ccccc12

Procedure:
A solution of indolizine-1,3-dicarboxylic acid 3-benzyl ester 1-tert-butyl ester (400 mg, 1.14 mmol) and TFA (872 μl, 11.4 mmol) in CH2Cl2 (10 mL) was stirred at RT overnight. The reaction mixture was concentrated and the crude solid was taken-up in a mixture of MeOH and CH2Cl2, the precipitate was filtered-off and washed with a minimum of MeOH to give the desired compound as a white powder. The filtrate was concentrated and purified by flash column chromatography on silica gel (CH2Cl2 to CH2Cl2/MeOH 95:5) to give again the desired compound. TLC, Rf (CH2Cl2/MeOH 9:1)=0.6; MS (LC/MS): 296.0 [M+H]+ 294.1 [M−H]−; tR (HPLC conditions a): 3.64 min.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[C:13]([CH:16]=O)[CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].Cl.[NH:19]1[C:23]([CH:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)=[CH:22][CH:21]=[N:20]1>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.[BH3-]C#N.[Na+]>[NH:19]1[C:23]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:16][C:13]3[CH:12]=[CH:11][C:10]4[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]([CH2:1][CH3:2])[C:15]=4[CH:14]=3)[CH2:25]2)=[CH:22][CH:21]=[N:20]1
Reactant: CCn1c2ccccc2c2ccc(C=O)cc21
Reactant: c1cc(C2CCCNC2)[nH]n1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1CCOC1
Product: CCn1c2ccccc2c2ccc(CN3CCCC(c4ccn[nH]4)C3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
A 100-mL 3-necked round-bottom flask was charged with a solution of 9-ethyl-9H-carbazole-2-carbaldehyde (1.12 g, 5.02 mmol, 1.00 equiv) in THF (50 mL). To this was added 3-(1H-pyrazol-5-yl)piperidine hydrochloride (940 mg, 5.01 mmol, 1.00 equiv), Ti(OiPr)4 (2 g, 7.04 mmol, 1.40 equiv) and TEA (660 mg, 6.52 mmol, 1.30 equiv). The resulting solution was stirred at room temperature overnight. To the mixture was then added NaBH3CN (1.26 mg, 0.02 mmol, 4.00 equiv). The resulting solution was stirred at room temperature for 4 hours. Upon completion, the reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (4×50 mL) and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The residue was purified by silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording 2-((3-(1H-pyrazol-5-yl)piperidin-1-yl)methyl)-9-ethyl-9H-carbazole as a white solid (0.3 g, 17%). LCMS:[M+H]+ 359. 1H NMR (CDCl3, 300 MHz) δ 8.08 (t, 2H), 7.50-7.41 (m, 4H), 7.28-7.21 (m, 2H), 6.05 (d, 1H), 4.40 (q, 2H), 3.80 (q, 2H), 3.16 (s, 1H), 2.72 (br, 4H), 1.88 (s, 1H), 1.65 (d, 3H), 1.46 (t, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([O:21]CC)=[O:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].Cl>CCO>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:19]([OH:21])=[O:20])=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A solution of ethyl 5,6-diphenylpyridine-2-carboxylate (Compound 21, 40 mg, 0.13 mmol) and LiOH (1N, 1 ml) in EtOH (2 ml) was stirred at room temperature overnight. The mixture was acidified with 10% HCl, then extracted with EtOAc. The organic layer was washed with water, and brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (20-80% Ethyl acetate in hexane) to give title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CC(N(C)C)=O>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[N:9][NH:10][C:11]=4[CH3:12])[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCN(Cc3ccccc3)CC1)N2
Temperature: 100 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (100 mg, 0.45 mmol), 1-benzylpiperidin-4-one (0.093 mL, 0.50 mmol), CSA (125 mg, 0.54 mmol), MgSO4 (108 mg, 0.90 mmol) and DMA (1 mL) was stirred at 100° C. for 3 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, and then dried over Na2SO4. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, NH, 90:10 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH), then crystallized from MeOH/EtOAc/hexane to give the title compound (45 mg, 25%) as a yellow solid:
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].CCOCC>C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH3:14][O:13][C:11](=[O:12])[C:10]([C:9]([O:16][CH3:17])=[O:15])=[C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])[CH3:4]
Reactant: CCOC(=O)C(C)=O
Reactant: COC(=O)CC(=O)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C)=C(C(=O)OC)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
A mixture of ZnCl2 (53 g, 388 mmol) in acetic anhydride (120 mL) was stirred at r.t. for 2 h. The resulting solution was decanted, and to this solution was added ethyl pyruvate (25 g, 215 mmol) and dimethyl malonate (25 mL, 215 mmol). The resulting mixture was heated at 100° C. for 1 h, then left standing at r.t. for 16 h. Ether (300 mL) was added and the mixture was washed with ice water (5×300 mL) and saturated NaHCO3 (2×300 mL). The organic layer was dried over MgSO4 and concentrated to give a dark brown oil, which was distilled under reduced pressure to give 34.1 g of the title compound as an orange oil. 1H NMR (CDCl3, 200 MHz): δ=4.26 (q, 2H, J=7.0 Hz), 3.82 (s, 3H), 3.79 (s, 3H), 2.22 (s, 3H), 1.32 (t, 3H, J=7.2 Hz).
Reaction SMILES: I[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([NH:35][C:36]([NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[O:37])[CH:32]=[CH:33][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[F:41][C:40]([F:42])([F:43])[CH2:39][NH:38][C:36]([NH:35][C:31]1[CH:32]=[C:33]([C:2]2[N:6]3[N:7]=[CH:8][C:9]([C:11]4[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=4)[C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:5]3=[N:4][CH:3]=2)[CH:34]=[CH:29][CH:30]=1)=[O:37]
Reactant: COC(=O)c1cccc(-c2cnn3c(I)cnc3c2)c1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (6.7 mg, 0.0095 mmol) was added to a mixture of methyl 3-(3-iodoimidazo[1,2-b]pyridazin-7-yl)benzoate (0.12 g, 0.32 mmol), N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (140 mg, 0.41 mmol) and sodium carbonate (67 mg, 0.63 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) and then the reaction vessel was evacuated under reduced pressure and refilled with nitrogen 3 times. The reaction was stirred at 100° C. overnight. To this mixture was added aqueous AcCN and then filtered, washed with aqueous AcCN, dried to provide the product (0.09 g). LCMS (M+H)+: m/z=470.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[CH3:21].[C:22]([C:24]1[CH:25]=[C:26]([C:30](O)=[O:31])[CH:27]=[N:28][CH:29]=1)#[N:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:30](=[O:31])[C:26]3[CH:25]=[C:24]([C:22]#[N:23])[CH:29]=[N:28][CH:27]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[CH3:21]
Reactant: N#Cc1cncc(C(=O)O)c1
Reactant: Cc1cc(-c2cc(N)cnc2OCC(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(NC(=O)c3cncc(C#N)c3)cnc2OCC(F)(F)F)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-methyl-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 57 a) and 5-cyano-3-pyridinecarboxylic acid, (CAN 887579-62-6) as starting materials; LC-MS (UV peak area/ESI) 98.7%, 445.0693 (M−H)−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:15])[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1>>[C:4]1([CH3:5])[CH:3]=[CH:2][CH:7]=[CH:6][C:15]=1[C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1
Reactant: Ic1ccccc1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccccc1-c1ccc(S)cc1

Procedure:
The general procedure was used to convert iodobenzene and p-toluenethiol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (388 mg, 97.0% yield). 1H NMR (300 MHz, CDCl3) δ 7.18 (dt, J=8.1, 2H; Ha, Ha′), 7.15–7.12 (m, 4H; He, He′, Hf, Hf′), 7.08 (m, 1H; Hg), 7.04–7.00 (d, J=7.34, 2H; Hc, Hc′), 2.22 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 138.05 (C4), 137.62 (C1′), 132.77 (C2, C6), 131.76 (C1), 130.55 (C3, C5), 130.23 (C2′, C6′), 129.52 (C3′, C5′), 126.87 (C4′), 21.62 (C7). Anal. Calcd. for C13H12S: C, 77.95; H, 6.04; S, 16.01; Found C, 77.78; H, 6.01; S, 16.19.
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cccc(-c2csc(NS(=O)(=O)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrobromide with 0.21 g of benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated as an oil upon neutralization and was thereupon again treated with active charcoal. The product separated upon renewed neutralization with concentrated hydrochloric acid. Recrystallization from 10 ml of 50% ethanol yeilded 0.06 g of N-[4-(3-nitro-phenyl)-thiazol-2-yl]-benzenesulfonamide as yellowish crystals.