Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[C:32]1[CH:33]=[N:34][CH:35]=[N:36][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[N:34]1[CH:33]=[C:32]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[O:13][C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)=[N:10][N:11]=3)=[CH:15][CH:16]=2)[CH:37]=[N:36][CH:35]=1
Reactant: Oc1ccc(-c2nnc(Nc3ccc(Cl)cc3)o2)cc1
Reactant: Brc1cncnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Clc1ccc(Nc2nnc(-c3ccc(Oc4cncnc4)cc3)o2)cc1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
4-{5-[(4-chlorophenyl)amino]-1,3,4-oxadiazol-2-yl}phenol (144.0 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (100.0 mg, 0.5 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 5-bromopyrimidine (79.5 mg, 0.5 mmol) was added, followed by anhydrous K2CO3 (34.5 mg, 0.25 mmol). Then the vial was capped and microwaved at 200° C. for 15 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (61.6 mg).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([C:12]3[CH:17]=[C:16]([S:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=3[O:28][CH2:29][CH2:30][CH3:31])[NH:11][C:5]=2[N:4]([CH2:32][CH2:33][CH3:34])[C:3]1=[O:35]>ClCCl>[CH3:1][N:2]([CH2:7][C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:35])[N:4]([CH2:32][CH2:33][CH3:34])[C:5]=2[NH:11][C:10]=1[C:12]1[CH:17]=[C:16]([S:18]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:28][CH2:29][CH2:30][CH3:31])[CH3:3]
Reactant: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1cc2c(=O)n(C)c(=O)n(CCC)c2[nH]1
Solvent: ClCCl
Product: CCCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1[nH]c2c(c1CN(C)C)c(=O)n(C)c(=O)n2CCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 190.2 %

Procedure:
A mixture of the title compound of Example 89 (30 mg, 0.06 mmol) and N,N-dimethylmethyleneiminium iodide (57 mg, 0.23 mmol) in anhydrous dichloromethane was stirred at room temperature overnight. The reaction mixture was purified by solid phase extraction using a Varian Bond Elut SCX cartridge (methanol for washing, methanol-ammonia for elution) to yield the title compound (32 mg, 95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=O)[C@H:10]([CH3:20])[CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[CH3:20][C@H:10]1[C@@H:11]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N1CCCC1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1COCCO1
Product: C[C@@H]1CNCC[C@@H]1N1CCCC1

Procedure:
The title compound was prepared in analogy to 193B, by reduction of (cis)-3-methyl-4-(2-oxo-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example 195B) with lithium aluminium hydride and subsequent deprotection with 4M hydrochloric acid in dioxane. MS: 169.2 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].C(N(CC)CC)C.CS(C)=O.ClCCl>O>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: COc1cc(CO)ccc1NC(C)=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C=O)ccc1NC(C)=O
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a mixture of 4-acetamido-3-methoxybenzyl alcohol (800 mg), triethylamine (2.07 g), dimethylsulfoxide (5 ml) and dichloromethane (2.5 ml) was added portionwise sulfur trioxide pyridine complex (1.3 g) in water bath, and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was poured into water, and extracted with dichloromethane. The organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 4-acetamido-3-methoxybenzaldehyde (653 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([OH:19])[CH2:16][CH:15]3[CH2:17][CH2:18][CH:8]2[CH2:9][C:10]23OCC[O:11]2)[CH:2]=1.Cl>C1COCC1.C([O-])(O)=O.[Na+].O>[OH:19][C:7]1([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:16][CH:15]2[CH2:17][CH2:18][CH:8]1[CH2:9][C:10]2=[O:11]
Reactant: OC1(c2cccnc2)CC2CCC1CC21OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CC2CCC1CC2(O)c1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Alcohol of step A (higher Rf isomer, 0.290 g, 1.11 mmol) was dissolved in THF (10 mL) under nitrogen. Hydrochloric acid (2.0 mL, 4.0 M aqueous solution, 8.0 mmol) was added and the mixture stirred for 4 hours at room temperature. The mixture was then diluted with NaHCO3/H2O and extracted twice with ethyl acetate. The extracts were washed with brine, dried over MgSO4, filtered and concentrated to provide a light yellow solid, 0.204 g (85%). The crude product 2 was used directly for the next step without further purification. 1H NMR (CDCl3) □δ□□ 8.74 (s, 1H), 8.52 (d, 1H), 7.72 (dt, 1H), 7.30 (dd, 1H), 2.66 (dt, 1H), 2.53 (m, 2H), 2.41 (t, 1H), 2.18 (t, 1H), 2.13 (d, 1H), 2.09 (m, 1H), 1.99 (m, 1H), 1.89 (m, 1H), 1.62 (m, 2H). Step C
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@@H:19]1Br)(=[O:16])[CH3:15]>C(OCC)C.O>[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@H:19]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)(=[O:16])[CH3:15]
Reactant: Brc1cccc(Br)c1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Solvent: BrCCBr
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Br)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
Magnesium (0) (400 mg) was suspended in 17 mL of anhydrous diethyl ether, and to the suspension was added 100 μL of 1,2-dibromoethane. 1,3-dibromobenzene (3.8 g, 16.08 mmol) was added at a rate to keep a moderate reflux. After Grignard formation was complete (magnesium consumed and the reaction cooled), 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.34 g, 0.80 mmol in 8 mL of anhydrous diethyl ether) was added drop-wise. The reaction was refluxed for 5 h, cooled to room temperature and poured into a separatory funnel with 20 mL of water. The flask was rinsed with 50 mL of diethyl ether and 3 mL of acetic acid (to dissolve the magnesium salts) and added to the seperatory funnel. The layers were separated and the aqueous layer was collected and concentrated in vacuo. The white pasty solid was dissolved in 15 mL of pyridine and 10 mL of acetic anhydride. After 20 h at room temperate the reaction was poured into 150 mL of water and extracted into dichloromethane (3×150 mL). The organic layers were combine, washed with 1 N hydrochloric acid (3×50 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) to afford (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-(3-bromophenyl)-D-glucitol (0.178 g, 0.36 mmol, 45% yield) as a white foam; Rf 0.4 (40% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.44 (m, 2H) 7.25 (m, 2H), 5.27-5.35 (m, 1H), 5.21 (t, J=9.6 Hz, 1H), 5.03 (t, J=9.7 Hz, 1H), 4.36 (d, J=9.9 Hz, 1H), 4.23-4.32 (m, 1H) 4.08-4.18 (m, 1H) 3.80-3.85 (m, 1H) 2.09 (s, 3H), 2.06 (s, 3H), 1.99 (s, 3H), 1.84 (s, 3H) ppm; MS [M+H]+ 488.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:38])=[O:37])([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10].Br[C:41]1[CH:53]=[CH:52][C:44]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)=[CH:43][CH:42]=1.O>O1CCOCC1.C(Cl)Cl.[Pd+2]>[CH3:7][C@@:8]([S:36]([CH3:39])(=[O:37])=[O:38])([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:41]2[CH:53]=[CH:52][C:44]([O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:43][CH:42]=2)=[CH:25][CH:26]=1)[C:9]([NH:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)=[O:10]
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: CC1(C)OB(c2ccc(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@](CCc1ccc(-c2ccc(OC3CCCCO3)cc2)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O

Procedure:
Palladium (II) EnCat (575 mg, 0.22 mmol) was added to a mixture of potassium carbonate (892 mg, 3.1 mmol), (2R)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanamide (1.01 g, 2.1 mmol), (i.e. compound VIIa, which was prepared as in Preparation 8) and 2-(4-bromophenoxy)tetrahydro-2H-pyran (819 mg, 3.18 mmol) in dioxane:water (20 mL, 1:1) in a 50 mL flask and the reaction was heated at 90° C. overnight. The reaction was filtered and the resin was washed with ethyl acetate (50 mL) and water (50 mL). The organic layer was separated and aqueous layer extracted with ethyl acetate (2×100 mL). The combined organics were washed with saturated aqueous sodium bicarbonate (100 mL), dried (MgSO4), filtered and concentrated in vacuo to furnish the crude product. The material was dissolved in a minimum amount of DCM and loaded onto an Analogix SF25-40 g column and eluted with 100% heptane (500 mL) followed by increasing EtOAc in heptane 20%-30%-50% over 500 mL volumes. The title compound was obtained as a white solid (830 mg, 74.4%) LC-MS m/z 530.8 (M−1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[CH2:9][C:10]#[CH:11])(=O)=O.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][CH2:6][CH2:7][C:8]([CH3:13])([CH3:12])[CH2:9][C:10]#[CH:11])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: C#CCC(C)(C)CCOS(C)(=O)=O
Product: C#CCC(C)(C)CCNC(C)(C)C

Procedure:
A solution of 1.3 g of 24b in 15 ml of tert.butylamine, was heated in a closed vessel at an oil bath at 70° C. for 4 days. The reaction was concentrated (rotavap, 150 mB, 40° C.) and then diluted with water and acidified with 1N HCl. The organic layer was washed twice with ether. The aqueous phase was made alkaline (2N NaOH) and extracted with diethylether. The organic material was dried and concentrated (100 mm, 40° C.) to give 960 mg of amine 24c, as a colorless oil. NMR (CDCl3) δ 1.00 (s, 6, 2×CH3), 1.11 (s, 9, tertC4H9), 1.47 (m, 2, CH2), 1.98 (t, 1, acetylene), 2.10 (d, 2, CH2), 2.55 (m, 2, CH2).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23]Cl.Cl>CN(C=O)C.O>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:23][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2([CH2:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[C:4]1=[O:18]
Reactant: O=C1CC2(C(=O)N1)C(=O)Nc1ccccc12
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC2(C(=O)N1)C(=O)N(Cc1ccc(Cl)c(Cl)c1)c1ccccc12
Temperature: 90 °C
Yield: 16.5 %

Procedure:
Sodium hydride (1.1 g.; 23 mM; 50% w/w oil dispersion) was added to a stirred solution of spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (2.1 g.; 9.7 mM) in DMF (40 ml.), under an atmosphere of nitrogen. The mixture was stirred until effervescence had ceased and then heated to approximately 90° C. 3,4-Dichlorobenzyl chloride (2.2 g., 11.2 mM) was added dropwise. The reaction mixture was then allowed to cool to ambient temperature, stirred for 16 hours, and poured into water. The aqueous mixture was acidified (concentrated hydrochloric acid) and extracted with ethyl acetate (2×150 ml.). The combined extracts were washed with water (3×150 ml.), brine (150 ml.), dried MgSO4) and evaporated. The residual oil was purified by chromatography on silica gel (150 g.) using an increasing gradient of ethyl acetate in toluene as eluant. Fractions were monitored by TLC (SiO2 : 50% v/v EtOAc/toluene) and those containing the major component (relative flow value: 0.5) were evaporated to give 1'-(3,4-dichlorobenzyl)-spiro[pyrrolidine-3,3'-indoline]-2,2',5-trione (0.6 g.), m.p. 205°-207° C. (recrystallised twice from MeOH).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=3)[N:10](COCCOC)[N:9]=2)=[CH:4][CH:3]=1.[CH:26](=O)[CH3:27]>C(O)C.[Pd].[C]>[CH2:26]([NH:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:27]
Reactant: COCCOCn1nc(-c2ccc(F)cc2)c2cc([N+](=O)[O-])ccc21
Reactant: CC=O
Agent: [Pd]
Solvent: CCO
Product: CCNc1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 1-{[3-(4-fluorophenyl)-5-nitro(1H-indazolyl)]methoxy}-2-methoxyethane (100 mg, 0.29 mmol) in ethanol (30 mL, containing a contaminant of acetaldehyde) was added a scoup of Pd/carbon. The reaction was stirred overnight at room temperature under an atmosphere of hydrogen. It was filtered over celite and the solution concentrated to an oil. The oil was taken up in methanol (20 mL) and 6N HCl (20 mL) and heated to 75° C. for 3 hours. The solution was concentrated under vacuo, added to saturated bicarbonate (100 mL), and extracted with ethyl acetate (3×30 mL). The organic layers were dried (Na2SO4), concentrated to an oil and chromatographed on silica gel, eluting with 50% ethyl acetate/hexane to give the title compound (8 mg, 11% yield). 1H NMR (CDCl3) δ 10.4 (br s, 1H), 7.91 (dd, 2H), 7.26-7.17 (m, 3H), 6.99 (s, 1H), 6.84 (dd, 1H), 3.21 (q, 2H), 1.31 (t, 3H); ES-MS (m/z) 256 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:11]([N:19]=[C:20]=[O:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCOCC1>[C:7]([C:6]1[C:5]([CH3:9])=[C:4]([CH3:10])[S:3][C:2]=1[NH:1][C:20]([NH:19][C:11](=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:21])#[N:8]
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Cc1sc(N)c(C#N)c1C
Solvent: C1COCCO1
Product: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of 2-amino-4,5-dimethylthiophene-3-carbonitrile (1680 g, 11.04 mol) in 1,4-dioxane (42 L) was added benzoylisocyanate (1624 g, 11.04 mol). The reaction mixture was then stirred at room temperature under nitrogen overnight. The resulting precipitate was collected by filtration, washed with 1,4-dioxane (3×1.7 l) and heptane (3×1.7 L), and dried under vacuum overnight to give N-(3-Cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide as a white solid (2800 g, 84.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.10 (s, 3H), 2.24 (s, 3H), 7.52-7.56 (m, 2H), 7.64-7.69 (m, 1H), 8.01-8.03 (m, 2H), 11.57 (brs, 1H), 12.05 (brs, 1H). MS 300 (MH+).
Reaction SMILES: [C:1]([C:3]1[C:4]([N:9]=[CH:10][N:11](C)C)=[N:5][CH:6]=[N:7][CH:8]=1)#[N:2].N[C:15]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.NC1C=C(C)C=CC=1SC1C=CC(O)=CC=1.C(C1C(N=CN(C)C)=NC(SCC)=NC=1)#N>>[CH2:22]([O:21][C:19]1[CH:18]=[CH:17][C:16]([S:29][C:30]2[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=2)=[C:15]([NH:2][C:1]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][CH:8]=3)[N:9]=[CH:10][N:11]=2)[CH:20]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)C=Nc1ncncc1C#N
Reactant: Nc1cc(OCc2ccccc2)ccc1Sc1ccc(O)cc1
Agent: CCSc1ncc(C#N)c(N=CN(C)C)n1
Agent: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Product: Oc1ccc(Sc2ccc(OCc3ccccc3)cc2Nc2ncnc3ncncc23)cc1

Procedure:
The product from Example 194A was reacted with the product from Example 27A according to the procedure from Example 156C substituting the product from Example 27A for the product from Example 6c and substituting the product from Example 194A for the product from Example 156B to provide the crude product which was purified by HPLC with NH4OAc to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 5.10 (s, 2H), 6.63 (d, J=8.46 Hz, 2H), 6.94-7.05 (m, 1H), 7.10 (d, J=8.82 Hz, 2H), 7.18 (d, J=7.72 Hz, 2H), 7.29-7.51 (m, 5H), 9.05 (m, 1H), 9.63 (s, 1H), 9.92 (s, 1H), 10.66 (s, 1H); MS (ESI−) m/z 452 (M−H)−.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[Cl-].[CH3:11][O:12][C:13]([C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][NH2+:16]1)=[O:14].Cl[C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>C(#N)C>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[N:16]1[CH2:17][CH2:18][CH2:19][CH2:20][C@H:15]1[C:13]([O:12][CH3:11])=[O:14]
Reactant: COC(=O)[C@@H]1CCCC[NH2+]1
Reactant: Clc1nc2ccccc2o1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyldiisopropylamine (6.52 ml) was added to a solution of (2S)-2-(methoxycarbonyl)piperidinium chloride (3.057 g) [see Preparation 1] and 2-chlorobenzoxazole (2.13 ml) in acetonitrile (50 ml). The reaction mixture was stirred at room temperature for 18 hours and then at 50° C. for a further 2 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water, the organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 80:10:0, changing to 0:100:0, followed by 0:95:5, by volume, hexane:ethyl acetate:methanol, to afford methyl (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylate (3.18 g) as a solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[NH:6][C:5](=[O:16])[CH:4]=1.[F-].[Cs+].I[CH:22]([CH3:24])[CH3:23]>CN(C=O)C>[NH2:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([O:16][CH:22]([CH3:24])[CH3:23])[CH:4]=[C:3]2[C:2]([F:18])([F:17])[F:1]
Reactant: O=c1cc(C(F)(F)F)c2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CC(C)I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C(F)(F)F)c2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
In a 250-mL r.b. flask, a solution of 4-trifluoromethyl-6-nitroquinolinone (structure 1 of Scheme I) (3.78 g, 14.6 mmol) in DMF (75 mL) was treated with CsF (12.41 g, 73 mmol, 5.0 equiv.) and 2-iodopropane (11.09 g, 73 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature (rt) for 18 h. The reaction mixture was quenched with H2O (100 mL) and extracted with EtOAc (3×200 mL). The combined EtOAc extracts were washed with saturated aqueous NH4Cl solution (300 mL), H2O (300 mL) and brine (300 mL). Dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 5×20 cm, 2% EtOAc in hexane as eluent) to afford 3.94 g (90%) of the 2-isopropoxyquinoline as a white solid. Rf 0.81 (SiO2, 10% EtOAc-hexane). 1H NMR (400 MHz, CDCl3) 8.93 (s, 1H), 8.47 (dd, 1H, J=9.2, 2.5) 7.98 (d, 1H, J=9.2), 7.32 (s, 1H), 5.62 (septet, 1H, J=6.2), 1.45 (d, 1H, J=6.2).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11].C1COCC1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[N:25]=[C:26]=[S:27]>C(N(CC)CC)C>[NH2:3][C:4]1[C:8]([NH:9][C:26]([NH:25][C:19]2[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=2[Cl:17])=[S:27])=[C:7]([CH3:10])[S:6][C:5]=1[CH3:11]
Reactant: Cc1sc(C)c(N)c1N
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1sc(C)c(NC(=S)Nc2c(Cl)cccc2Cl)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 3,4-diamino-2,5-dimethylthiophene dihydrochloride, 30 ml of anhydrous THF and 0.49 g of triethylamine was stirred at room temperature for 30 minutes and then admixed with 0.569 g of 2,6-dichlorophenyl isothiocyanate. After the mixture had been heated to 40° C. for 30 minutes, it was stirred at room temperature for approx. 18 hours, the solvent was distilled off, the residue admixed with water and the precipitate filtered off and purified by column chromatography on silica gel using a mixture consisting of equal parts by volume of toluene and ethyl acetate. After the solvent had been distilled off, a foamy, amorphous product of m.p. 143–148° C. was obtained which, after melting, solidified again with a new m.p. of >300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-])=O.FC(F)(F)C(O)=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18]
Reactant: O=c1ccc(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccc(=O)[nH]n2)cc1C(F)(F)F

Procedure:
A mixture 10 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone in 50 ml. of trifluoroacetic acid is reduced with hydrogen and palladium on carbon to give 6-[4-amino-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone. The preceding compound is converted to 6-[4-fluoro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone by the procedure described in J. Org. Chem., 26, 468 (1961). The preceding compound is reacted with phosphorus oxychloride as described in Example 47 to give 3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine., which is reacted with formylhydrazine as described in Example 48 to give the product of the example.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][N:16]3[C:20](=[O:21])[CH2:19][S:18][C:17]3=[O:22])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:25](=O)[CH2:26][CH2:27][CH3:28].N1CCCCC1>C(O)C>[CH:25](=[C:19]1[S:18][C:17](=[O:22])[N:16]([CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:20]1=[O:21])[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(CCSc1cccc2nccn12)CCN1C(=O)CSC1=O
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCC(C)(C)CCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 339 mg (0.93 mmol) of 3-[5-(imidazo[1,2-a]pyridin-5-ylthio)-3,3-dimethylpentyl]thiazolidine-2,4-dione and 90 μl (1.0 mmol) of n-butyraldehyde in 5 ml of ethanol, 10 μl (0.1 mmol) of piperidine was added, followed by refluxing for 1.5 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/2) to yield 310 mg (74.2%, light yellow oily substance) of the desired product.