Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:23]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:15]=1I)#[N:2].[F:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[C:1]([C:3]1[CH:4]=[C:5]([S:23]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:15]=1[C:38]1[C:33]([F:32])=[N:34][CH:35]=[CH:36][CH:37]=1)#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccccc2)cc1I
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccccc2)cc1-c1cccnc1F
Reaction time: 0.08 h
Yield: 28.3 %

Procedure:
10 mg (0.02 mmol) of 3-cyano-4-((4-iodo-6-phenylpyridin-3-yl)oxy)-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (2-fluoropyridin-3-yl)boronic acid was added thereto, and then 2.0 mg (10 mol %) of Pd(PPh3)4, 5.6 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 3 mg (30% yield) of the title compound.
Reaction SMILES: [CH3:1][NH2:2].COS([CH2:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][NH:2][CH2:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1
Reactant: COS(=O)(=O)CCC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNCCC(Cc1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 22 °C
Reaction time: 8 h

Procedure:
Methylamine (37.2 ml of a 40% by weight aqueous solution, 481 mmole) was added to a 250 ml flask containing 4.47 g (12.0 mmole) of 3-phenyl-4-(4-trifluoromethylphenyl)butane sulfonic acid methyl ester dissolved in 50 ml of tetrahydrofuran. The resulting solution was stirred overnight at room temperature (22° C.) and concentrated under reduced pressure to provide a residue. The residue was dissolved in ethyl acetate and the resulting solution was washed with water and a saturated brine solution. The organic solution was dried over anhydrous sodium sulfate and the volatiles were removed under reduced pressure to provide 3.5 g of N-methyl-3-phenyl-4-(4-trifluoromethylphenyl)butanamine as an oil. A sample of the oil was crystallized from an acetone/diethyl ether solution containing 1.5 equivalents of concentrated hydrochloric acid to yield N-methyl-3-phenyl-4-(4-trifluoromethylphenyl)butanamine hydrochloride as white crystals. mp=156°-157.5° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C@H:32]([CH3:45])[C@H:33]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:34](O)=O)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C@H:32]([CH3:45])[C@@H:33]([C:34]1[O:20][N:19]=[C:17]([C@@H:10]2[CH2:11][C:12](=[N:14][O:15][CH3:16])[CH2:13][N:9]2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[N:18]=1)[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:30])([CH3:29])[CH3:28]
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc([C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 48 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (2S,3R)-3-tert-butoxy-2-[(tert-butoxycarbonyl)amino]butanoic acid, the title compound, 4-{[(2S,4EZ)-2-(5-{(1S,2R)-2-tert-butoxy-1-[(tert-butoxycarbonyl)amino]propyl}-1,2,4-oxadiazol-3-yl)-4-(methoxyimino)pyrrolidinyl]carbonyl}-1,1′-biphenyl, was obtained in 48% yield (85.9% purity by HPLC).
Reaction SMILES: Br[C:2]1[N:18]([CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]2)[C:5]2[C:6]([O:11][CH:12]([CH:14]3[CH2:17][CH2:16][CH2:15]3)[CH3:13])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=2[N:3]=1.[C:27]1([C@@H:33]2[CH2:38][O:37][CH2:36][CH2:35][NH:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[F-].[Cs+]>CS(C)=O.O>[Cl:10][C:8]1[N:7]=[C:6]([O:11][CH:12]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH3:13])[C:5]2[N:18]([CH2:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([CH3:26])[CH2:22][CH2:21]3)[C:2]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][C@H:33]3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:3][C:4]=2[CH:9]=1
Reactant: c1ccc([C@@H]2COCCN2)cc1
Reactant: CC(Oc1nc(Cl)cc2nc(Br)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Product: CC(Oc1nc(Cl)cc2nc(N3CCOC[C@H]3c3ccccc3)n(C[C@H]3CC[C@H](C)CC3)c12)C1CCC1
Temperature: 125 °C

Procedure:
To a solution of 2-bromo-6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine (1.5 g, 3.40 mmol) in DMSO (15 mL), in a microwave tube was added (R)-3-phenylmorpholine (797 mg, 4.77 mmol) and cesium fluoride (3.6 g, 23.8 mmol). The reaction was heated at 125° C. in a microwave for 45 mins. The reaction was then diluted with water (50 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 8-10% EtOAc/petroleum ether) to yield (3R)-4-(6-chloro-4-(1-cyclobutylethoxy)-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridin-2-yl)-3-phenylmorpholine. MS ES/APCI calc'd. for C30H39ClN4O2 [M+H]+ 523. found 523.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1.Cl.C(=O)([O-])[O-].[NH4+:36].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][S:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29](=[NH:36])[NH2:30])[CH:24]=1
Reactant: Cn1c(COc2cccc(C#N)c2)nc2cc(NS(=O)(=O)c3ccccc3)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(COc2cccc(C(=N)N)c2)nc2cc(NS(=O)(=O)c3ccccc3)ccc21

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[(3-cyanophenyl)-oxymethyl]-5-(benzenesulphonylamino)-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]([C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:27])[C:25]=1[Cl:26])[C:22](=[O:28])[C:21]([CH2:32][CH:33]=[C:34]([Cl:36])[CH3:35])([CH2:29][CH2:30][CH3:31])[CH2:20]2)(C(OCC)=O)[C:7]([O:9]CC)=[O:8])=[O:4].[OH-].[Na+].Cl>CO.O>[Cl:26][C:25]1[C:24]([Cl:27])=[C:23]2[C:19]([CH2:20][C:21]([CH2:32][CH:33]=[C:34]([Cl:36])[CH3:35])([CH2:29][CH2:30][CH3:31])[C:22]2=[O:28])=[CH:18][C:17]=1[CH:6]([CH2:5][C:3]([OH:4])=[O:2])[C:7]([OH:9])=[O:8]
Reactant: CCCC1(CC=C(C)Cl)Cc2cc(C(CC(=O)OC)(C(=O)OCC)C(=O)OCC)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC1(CC=C(C)Cl)Cc2cc(C(CC(=O)O)C(=O)O)c(Cl)c(Cl)c2C1=O
Yield: 94 %

Procedure:
Diethyl methoxycarbonylmethyl[6,7-dichloro-2-(3-chloro-2-butenyl)-2,3-dihydro-1-oxo-2-propyl-1H-inden-5-yl]malonate (10.7 g, 0.019 mole) was stirred at reflux for 21/2 hours in a mixture of methanol (120 ml), water (120 ml) and sodium hydroxide (6 g). The solution was cooled, diluted with water, acidified with hydrochloric acid, and extracted with methylene chloride. The organic extracts were washed with water, dried over MgSO4 and concentrated to obtain 8.0 g of the product as a gum.
Reaction SMILES: [NH2:1][C:2]([CH3:20])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:19])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2=[N:7]1)[C:3]#[N:4].[O:21]([C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:19][C:12]1[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]2[C:9]([CH:11]=1)=[N:10][N:6]([CH2:5][C:2]([NH:1][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:36][CH:35]=1)([C:3]#[N:4])[CH3:20])[N:7]=2
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)cc(C(F)(F)F)c2n1
Product: CC(C#N)(Cn1nc2cc(Cl)cc(C(F)(F)F)c2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-chloro-4-trifluoromethyl-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 32) and 4-phenoxybenzoyl chloride (0.10 mL), the title compound was isolated as a white solid (95 mg, 58%). Rf=0.75 (1:1 EA/heptane). MS (ES): M/Z [M+H]=500. NMR: (400 MHz, DMSO-d6): 1.76 (s, 3H), 2.47 (s, 3H), 5.47 (d, J=13.3 Hz, 1H), 5.57 (d, J=13.3 Hz, 1H), 7.04-7.12 (m, 4H), 7.22 (t, J=7.4 Hz, 1H), 7.97 (s, 1H), 8.57 (s, 1H) and 8.69 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −61.41 (s, 3F).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][CH:18]=1>C1COCC1>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=2)([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: COc1cccc([Mg]Br)c1
Reactant: CC(=O)c1ccc(I)cc1
Solvent: C1CCOC1
Product: COc1cccc(C(C)(O)c2ccc(I)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-iodoacetophenone (2 g, 7.97 mmol) in THF (20 ml) was immersed in an ice-bath and (3-methoxyphenyl)magnesium bromide 1M in THF (23.90 ml, 23.90 mmol) was added slowly by syringe. The reaction mixture was stirred at r.t. for 3 hrs. The reaction mixture was quenched with 20 ml aqueous saturated NH4Cl solution and diluted with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by automated column chromatography (n-heptane (isom. mixture)/ethyl acetate). Organic solvents were removed to obtain title compound as yellowish oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19]>>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Product: CC(=O)N1CCN(c2ccc(NS(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1-Acetyl-4-(4-aminophenyl)piperazine (10.96 g) in ice-cold pyridine (100 ml) was added methanesulphonyl chloride (6.3 g) dropwise. The mixture was then stirred at ambient temperature overnight and the pyridine removed in vacuo. The residue was triturated with aqueous sodium bicarbonate, and the resulting solid was washed (water) and crystallized from methanol/ethyl acetate (charcoal). The yield of the title compound was 9.97 g, m.p. 165°-7°.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([C:7]2[CH:20]=[CH:19][C:10]([C:11]([CH:13]3[CH2:18][CH2:17][N:16]([CH2:22][CH2:23][C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)C1CCNCC1
Reactant: BrCCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccc2)cc1)C1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A solution of 10.4 g of 4-(4-phenylbenzoyl)-piperidine, 8.8 g of 3-(2-bromoethyl)indole and 4.5 g of triethylamine in 300 ml of dimethylformamide is treated according to the manipulative procedure outlined in Example 3(b) to produce 3-{2-[4-(4-phenylbenzoyl)piperidyl]-ethyl}indole. The indole is recrystallized twice from an ethanol-water mixture (one charcoal treatment), thrice from a pyridine-water mixture, and twice from an acetone-water mixture to give the product, mp 189°-192° C.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([Si]([O:26][CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH:35]([CH3:37])[CH3:36])[C:31]([F:38])=[C:30]([O:39][CH:40]([CH3:42])[CH3:41])[CH:29]=1)(C)C)(C)(C)C>C1COCC1>[F:38][C:31]1[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:33][C:28]([CH2:27][OH:26])=[CH:29][C:30]=1[O:39][CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)Oc1cc(CO[Si](C)(C)C(C)(C)C)cc(OC(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(CO)cc(OC(C)C)c1F
Reaction time: 1 h
Yield: 116.8 %

Procedure:
TBAF (1M in THF) (1.35 mL, 1.35 mmol) was added to a solution of tert-butyl(4-fluoro-3,5-diisopropoxybenzyloxy)dimethylsilane (6) (600 mg, 1.35 mmol) in THF at 0° C. and the mixture was stirred at this temperature for 1 h. The mixture was partitioned between NH4Cl (satd. aq.) (50 mL) and EtOAc (100 mL). The phases were separated and the organic solution was washed with brine (50 mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (40 g, 0-50% EtOAc in isohexane) to afford (4-fluoro-3,5-diisopropoxyphenyl)methanol (7) (382 mg, 100%) as a colourless oil.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:27]=[N:28][C:29]([C:32]#[C:33][Si](C)(C)C)=[CH:30][CH:31]=2)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:27]=[N:28][C:29]([C:32]#[CH:33])=[CH:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: C[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(-c2ccc(Cl)cc2)nn1
Reaction time: 0.5 h

Procedure:
1.10 g (3.49 mmol) TBAF are added at 0° C. to a solution of 1.00 g (3.49 mmol) 3-(4-chloro-phenyl)-6-trimethylsilanylethynyl-pyridazine in 10 mL DCM. The ice bath is removed and the reaction solution is stirred for 30 min. Water is added and the aqueous phase is extracted with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The product is reacted without any further purification.
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[C:24]([F:35])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:9])=C.Cl.[OH-].[Na+]>C(O)C.O>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=2[Cl:34])=[C:24]([F:35])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:9]
Reactant: C=COCCONC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NOCCO)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide 11s (0.039 g, 0.068 mmol) is dissolved in ethanol (2 mL) and aqueous 2 M HCl (200 uL) is added. The reaction mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted with water and then neutralized with aqueous 2 M NaOH (˜200 μL) until pH 7 and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and brine in a separatory funnel and the layers separated. The ethyl acetate layer is dried (Na2SO4) and concentrated under reduced pressure to yield 0.034 g (91%) of the pure desired product as an off-white solid. MS ESI (+) m/z 541, 543 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.75 (s, 1H), 7.49 (d, 1H), 7.18 (dd, 1H), 6.40 (dd, 1H), 4.40 (dd, A of ABX pattern, 1H), 4.28 (dd, B of ABX pattern, 1H), 3.92 (m, X of ABX pattern, 1H), 3.66 (t, 2H), 3.35 (m, 1H), 1.89 (m, 1H), 1.76 (m, 1H), 2.28 (s, 3H), 1.54 (m, 3H), 1.30 (m, 1H). 19F NMR (376 MHz, CD3OD) −134.87 (s).
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:21]#[N:22]>>[C:21]([C:20]1[CH:23]=[CH:24][C:25]2[N:26]=[C:1]([C:3]3[CH:16]=[CH:15][C:6]([CH:7]=[C:8]4[S:12][C:11](=[O:13])[NH:10][C:9]4=[O:14])=[CH:5][CH:4]=3)[NH:17][C:18]=2[CH:19]=1)#[N:22]
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Reactant: N#Cc1ccc(N)c(N)c1
Product: N#Cc1ccc2nc(-c3ccc(C=C4SC(=O)NC4=O)cc3)[nH]c2c1

Procedure:
5-Cyano-2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]benzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 3,4-diaminobenzonitrile by following General Procedure 2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)=[O:6].C([O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])C.COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:3][C:2]=1[C:34]1[CH:35]=[CH:36][C:31]([C:29]([OH:30])=[O:28])=[CH:32][CH:33]=1
Reactant: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1Br
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)cc2)cc1-c1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
A mixture of 3-Bromo-4-methoxy-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-benzamide (748 mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (538 mg) in 2:1 DME:water (15 ml) containing cesium carbonate (1.21 mg) and tetrakis(triphenylphosphine)palladium0 (220 mg) was heated to reflux for 18 h. The mixture was cooled and then evaporated. The residue was then stirred in ethanol (8 ml) and 2M NaOH (4 ml) at room temp for 16 h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting solid was collected by filtration and dried (528 mg)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[N:29]1([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.N1CCCCC1>CN(C)C=O>[N:29]1([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:40]/[C:18](=[C:6]3\[C:5](=[O:28])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=4)/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:41][CH:42]=2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
1.5 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 1.1 g of 4-(piperidin-1-yl-methyl)-aniline are dissolved in 15 ml of dimethylformamide and stirred for 45 minutes at 100° C. After cooling 5.0 ml of piperidine are added and the mixture is stirred for another 3 hours at room temperature. The solvent is removed and the residue purified over an aluminium oxide column (activity: 2-3) with methylene chloride/ethanol (100:3) as eluant.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[N:12]=1.[Cl:24]N1C(=O)CCC1=O>CN(C)C=O>[Cl:24][C:10]1[S:9][C:8]([N:3]2[C:2]([CH3:23])([CH3:1])[CH2:6][O:5][C:4]2=[O:7])=[N:12][C:11]=1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2csc(N3C(=O)OCC3(C)C)n2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(N3C(=O)OCC3(C)C)sc2Cl)cc1
Reaction time: 120 h

Procedure:
Methyl 4-[2-(4,4-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-1,3-thiazol-4-yl]benzoate, prepared in Example 129, and N-chlorosuccinimide are combined in dimethylformamide (5 mL). The mixture is stirred for 5 days and partitioned between water and ethyl acetate. The combined organic layers are dried over magnesium sulfate and concentrated onto silica gel. The residue is purified by silica gel Flash Chromatography to give the title compound. The melting point is anticipated to be 152-155° C.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([CH3:16])[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]#[N:15].[OH-].[K+]>>[C:1]1(=[C:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH3:16])[C:14]#[N:15])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: Cc1ccccc1CC#N
Agent: [K+]
Agent: [OH-]
Product: Cc1ccccc1C(C#N)=C1CCCC1
Yield: 11.7 %

Procedure:
The procedure outlined in example 1 is repeated with cyclopentanone (14.3 g, 0.17 mol), o-tolylacetonitrile (13.1 g, 0.10 mol) and KOH (1.12 g, 0.02 mol). Short path distillation of the crude at 0.05 mbar/124-130° C. yields 5.30 g (27% yield). The product is contaminated with α,α′-dicyclopentylidenecyclopentanone. It is further purified by FC on SiO2 to yield 2.3 g of oily product (10% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[O:25]C)[C:18]=3[CH2:27][CH3:28])=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:13][C:14]([C:17]3[C:18]([CH2:27][CH3:28])=[C:19]([CH2:23][CH:24]=[O:25])[CH:20]=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCc1c(/C=C/OC)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 75 °C
Yield: 100 %

Procedure:
To a mixture of 2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3-thiazole (D77) (500 mg) in tetrahydrofuran (THF) (100 mL) under nitrogen was added HCl (0.805 mL). The reaction was heated to 75° C. for 3 h. The mixture was concentrated to give the crude product [3-(2-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3-thiazol-5-yl)-2-ethylphenyl]acetaldehyde (D78) (483 mg) as a brown oil. MS (ES): C22H22ClNO2S requires 399. found 400.1 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Reactant: c1c[nH]cn1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.