Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-:1].[Cl:2][C:3]1[CH:28]=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC1([CH:33]([C:39]([CH:41](N2C=NC=N2)[C:42]2(Cl)[CH2:44]C2)=O)[N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)CC1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:41]1([C:39](=[CH:5][C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]=2[Cl:2])[CH2:33][N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[CH2:42][CH2:44]1
Reactant: [Cl-]
Reactant: O=C(C(n1cncn1)C1(Cl)CC1)C(n1cncn1)C1(Cl)CC1
Reactant: Clc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccccc1C=C(Cn1cncn1)C1(Cl)CC1
Reaction time: 1 h
Yield: 77.1 %

Procedure:
36.6 g (326 mmol) of potassium tert.-butylate are added at 0° C. with stirring, to a solution of 115 g (271 mmol) of 2-chlorobenzyl-triphenylphosphonium chloride in 600 ml of tetrahydrofuran. After the addition has ended, stirring is continued for one hour at 40° C. A solution of 50.4 g (271 mmol) of 1-chlorocyclopropyl-(1,2,4-triazol-1-yl)-methyl ketone in 300 ml of tetrahydrofuran is subsequently added dropwise at 30° C. with stirring. The reaction mixture is stirred for 16 hours at room temperature and then poured into saturated, aqueous ammonium chloride solution. The phases are separated, the aqueous phase is extracted several times using ethyl acetate, and the combined organic phases are dried over sodium sulphate and concentrated by stripping off the solvent under reduced pressure. The residue which remains is chromatographed on silica gel using a mixture of cyclchexane:ethyl acetate=2:1 as eluent. In this manner, 61.5 g (77% of theory) of 2-(1-chlorocyclopropyl)-1-(1,2,4 -triazol-1-yl)-3-(2-chlorophenyl)-2-propene (E/Z isomer mixture) are obtained in the form of a solid of melting point 82°-85° C.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[F:31][C:32]([F:43])([F:42])[CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>>[F:31][C:32]([F:42])([F:43])[CH2:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Nc1ccc(OCC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2

Procedure:
Brown solid. MS (ESI): 553.12 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(2,2,2-trifluoro-ethoxy)-phenylamine.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][Si](C)(C)C)=[N:29][CH:30]=1)=[O:24])[CH3:21].C([O-])(=O)C.[K+].O>O1CCOCC1>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:32]=2)=[N:29][CH:30]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)nc1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1ccc(-c2cc3cc(SC)cnc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a solution of 2-benzenesulfonylamino-5-methylthio-3-iodo-pyridine (100 mg) in 1,4-dioxane (2.5 ml), 5-ethoxycarbonyl-2-trimethylsilylethynylpyridine (185 mg), bistriphenylphosphine palladium dichloride (9 mg), cuprous iodide (5 mg) and potassium acetate (37 mg) were added successively and the mixture was stirred in a sealed tube at 100° C. for 15 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=2:1) to obtain 110 mg of the desired product as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:16](Cl)(Cl)=[O:17]>C(Cl)(Cl)Cl.O1CCCC1>[CH3:15][O:14][C:8]1[C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]2[NH:1][C:16](=[O:17])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: COc1cc(C(=O)O)c(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc2c(=O)oc(=O)[nH]c2cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
2.0 g (9.4 mmol) of 2-amino-5-methoxy-4-nitrobenzoic acid were dissolved in 20 ml of chloroform and 10 ml of tetrahydrofuran, and 20 ml of 20% strength phosgene solution (1.8 M in toluene) were added. After 3 hours under reflux, a further 10 ml of phosgene solution were added at 60° C., and the mixture was stirred at 60° C. for a further 12 hours. The phosgene was distilled off and the residue was concentrated in vacuo after addition of toluene several times. 2.2 g (100%) of the desired product were obtained.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>ClCCl.O>[C:19]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(=O)Cl
Reactant: CC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NC(C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
22.27 g (250 mmol) of D,L-alanine and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred at room temperature for 1 hour and at 40° C. for one hour. After cooling to −10° C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred at −10° C. for 2 hours and at room temperature for one hour. With ice-cooling, 125 ml of water are added dropwise, and the reaction mixture is stirred at room temperature for 15 minutes. The aqueous phase is evaporated to dryness, the residue is triturated with acetone and the mother liquor is filtered off with suction. Following removal of the solvent, the residue is chromatographed. The resulting product is dissolved in 3N aqueous sodium hydroxide solution, and the resulting solution is evaporated to dryness. The residue is taken up in conc. HCl and again evaporated to dryness. The residue is triturated with acetone, the precipitated solid is filtered off with suction and the solvent is removed under reduced pressure. This gives 28.2 g (71%) of a viscous oil which crystallizes after some time.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)c2csc(N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (1.00 g, 2.14 mmol) (obtained as described in Reference Example 2(1)) in toluene (50 ml) was added a solution of 0.67M 1-methylpiperazine-trimethylaluminium in toluene (7.40 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 3 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 2 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(4-methylpiperazine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (941 mg, yield 85%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12]2)[N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:35](=[O:37])[CH3:36])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C[Si](Cl)(C)C.[CH2:43](O)[CH2:44]CC>>[C:35]([N:32]1[CH2:31][CH2:30][N:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:2]3[N:10]=[C:9]4[C:5]([N:6]=[CH:7][NH:8]4)=[C:4]([N:11]4[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH2:20][CH2:21][CH2:43][CH3:44])=[O:18])[CH2:12]4)[N:3]=3)=[CH:28][CH:27]=2)[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)C1CCCN(c2nc(Cl)nc3[nH]cnc23)C1
Reactant: CCCCO
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Product: CCCCOC(=O)C1CCCN(c2nc(Nc3ccc(N4CCN(C(C)=O)CC4)cc3)nc3[nH]cnc23)C1
Temperature: 135 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl 1-(2-chloro-9H-purin-6-yl)piperidine-3-carboxylate (108 mg, 0.349 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (115 mg, 0.525 mmol) and trimethylsilyl chloride (0.300 mL, 2.37 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (86 mg). MS 521.4 (M+H); UV 201.8, 272.8 nm.
Reaction SMILES: C(OC([NH:8][C:9]1([CH:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.[NH2:17][C:18]1[C:27]([F:28])=[C:26](F)[C:25]([F:30])=[C:24]2[C:19]=1[C:20](=[O:38])[C:21]([C:35]([OH:37])=[O:36])=[CH:22][N:23]2[C@@H:31]1[CH2:33][C@@H:32]1[F:34].[CH2:39](N(CC)CC)C>C(#N)C>[NH2:17][C:18]1[C:27]([F:28])=[C:26]([N:14]2[CH2:15][CH2:16][CH:12]([C:9]3([NH2:8])[CH2:11][CH2:10][CH2:39]3)[CH2:13]2)[C:25]([F:30])=[C:24]2[C:19]=1[C:20](=[O:38])[C:21]([C:35]([OH:37])=[O:36])=[CH:22][N:23]2[C@@H:31]1[CH2:33][C@@H:32]1[F:34]
Reactant: CCN(CC)CC
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Reactant: CC(C)(C)OC(=O)NC1(C2CCNC2)CC1
Solvent: CC#N
Product: Nc1c(F)c(N2CCC(C3(N)CCC3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2[C@@H]1C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A 242 mg (1.00 mmol) portion of 3-(1-tert-butoxycarbonylaminocyclopropyl)pyrrolidine (fr.2) was suspended in 10.0 ml of acetonitrile to which was subsequently added 212 mg (0.67 mmol) of 5-amino-6,7,8-trifluoro-[(1R,2S)-2-fluorocyclopropyl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 1.40 ml (6.70 mmol) of triethylamine, followed by overnight heating under reflux. After evaporation of the solvent, the resulting residue was mixed with chloroform, washed with water, 10% citric acid aqueous solution and saturated brine in that order, and then dried over anhydrous sodium sulfate, followed by evaporation of the solvent. Thereto was added 2 ml of concentrated hydrochloric acid, followed by 2 hours of stirring at room temperature. The reaction solution was mixed with 10 ml of water, washed with chloroform and then neutralized with sodium hydroxide aqueous solution. This was extracted with chloroform and dried over sodium sulfate, and then the solvent was evaporated. Thereafter, the resulting residue was recrystallized from ethanol-diisopropyl ether to yield 292 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](O)=[O:6].BrC1C=C(C=CC=1F)C([Cl:18])=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([Cl:18])=[O:6]
Reactant: O=C(Cl)c1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Product: O=C(Cl)c1ccc(Cl)c(Br)c1

Procedure:
3-Bromo-4-chlorobenzoyl chloride was prepared from 3-bromo-4-chlorobenzoic acid according to the procedure described in Example 183 for the synthesis of 3-bromo-4-fluorobenzoyl chloride.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][O:11][CH2:10][CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O[I:25](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II.IC1C=CC=CC=1>C(Cl)Cl.CCCCC>[I:25][C:4]1[CH:3]=[CH:2][C:1]([C@@H:7]2[CH2:12][O:11][CH2:10][CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccccc1
Agent: II
Solvent: ClCCl
Solvent: Ic1ccccc1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of (R)-tert-butyl 3-phenylmorpholine-4-carboxylate 7 (41.55 g, 157.66 mmol) in CH2Cl2 (400 mL) was added [bis(trifluoroacetoxy)-iodo]benzene (74.25 g, 172.7 mmol, 1.1 eq.) followed by I2 (40 g, 157.6 mmol, 1 eq.) at room temperature (The reaction was exothermic on this scale, the temperature was maintained at room temperature by means of a water bath!). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with CH2Cl2 (˜200 mL) and washed with sat. aq. NaHCO3 (2×750 mL), sat. aq. Na2S2O3 (2×500 mL) and brine (1 L). The organic layer was dried over Na2SO4 filtered and concentrated in vacuo leading to a brown oil containing the desired product. The residue was purified by automated column chromatography (silica column (1.6 kg); gradient heptanes/EtOAc 0 to 15%). The separation was not optimal, the product-containing fractions were concentrated affording a white solid contaminated with some (˜10%) iodobenzene and starting material. Trituration in pentane (2 mL/g) afforded material of sufficient purity (22.7 g, 58.3 mmol) was isolated in 37% yield.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[NH:4][C:3](=O)[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][Cl:25].O1CCOCC1.[ClH:32]>CC(C)=O.P(Cl)(Cl)(Cl)=O>[Cl:32][C:3]1[N:4]([CH2:21][CH2:22][CH2:23][CH2:24][Cl:25])[C:5](=[O:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH:2]=1
Reactant: ClCCCCBr
Reactant: O=C1COc2ccccc2C(=O)N1
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1c2ccccc2OC=C(Cl)N1CCCCCl
Temperature: 100 °C
Reaction time: 25 h
Yield: 45 %

Procedure:
5.0 g of 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione was dissolved in 100 ml of acetone, 7.8 g (2 equivalents) of potassium carbonate and 6.5 ml (2 equivalents) of 1-bromo-4-chlorobutane were added, and the mixture heated and refluxed for 8 hours. The resultant mixture was allowed to cool, then filtered. The filtrate was concentrated and the residue obtained was dissolved in 50 ml of phosphorus oxychloride. Further, 20 ml of 4N hydrochloride dioxane-solution was added and the mixture stirred at 100° C. for 25 hours. The phosphorus oxychloride was distilled off and a 10% aqueous sodium hydroxide solution added under ice cooling. The mixture was extracted with methylene chloride, then was washed with a saturated aqueous solution of potassium bicarbonate and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off and the crude product obtained was purified by silica gel column chromatograph (hexane:ethyl acetate=6:1) to obtain 4.4 g of the above-identified compound (yield 45%).
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=O)[C:6]=12)=[O:9]>C(O)C>[Cl:4][C:5]1[CH:15]=[CH:14][CH:13]=[C:7]2[C:6]=1[C:11](=[O:10])[NH:2][NH:3][C:8]2=[O:9]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH][nH]c(=O)c2c(Cl)cccc12
Yield: 58 %

Procedure:
A mixture of 3-chlorophthalic anyhydride (0.02 mol) and hydrazine hydrate (0.02 mol) in dry ethanol (50 ml) was heated to reflux in a reaction flask. Reflux continued for several hours until the 3-chlorophthalic anhydride disappeared and a white crystalline solid deposited on the walls of the flask. The solid was filtered and recrystallized from ethanol to yield 5-chloro-2,3-dihydrophthalazine1,4-dione in a yield of 58 percent.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[CH:3]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH2:35][CH2:36][NH:37][C:38](=[O:40])[CH3:39])=[CH:31][NH:32]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:34]=[C:33]2[C:29]([C:30]([CH2:35][CH2:36][NH:37][C:38](=[O:40])[CH3:39])=[C:31]([CH:17]([C:3]3[C:4](=[O:16])[O:5][CH:6]([CH2:7][CH2:8][CH2:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:2]=3[OH:1])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:32]2)=[CH:28][CH:27]=1
Reactant: O=C1C=C(O)C(CCCc2ccccc2)O1
Reactant: CC(=O)NCCc1c[nH]c2cc(F)ccc12
Reactant: O=Cc1ccccc1
Product: CC(=O)NCCc1c(C(C2=C(O)C(CCCc3ccccc3)OC2=O)c2ccccc2)[nH]c2cc(F)ccc12

Procedure:
Using general procedure C, 4-hydroxy-5-(3-phenyl-propyl)-5H-furan-2-one (Lit. 13) was reacted with benzaldehyde and N-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-acetamide (Example 18.1.) to give the title compound as pale red solid. MS: 525.2 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH3:38][N:39]1[CH2:44][CH2:43][N:42]([C:45](Cl)=[O:46])[CH2:41][CH2:40]1>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:45]([N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)=[O:46])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: CN1CCN(C(=O)Cl)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)N5CCN(C)CC5)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with 4-methylpiperazine-1-carbonyl chloride to give the title compound. LC/MS (M+H)+: 661. Ret. time: 1.46 min. (Condition G); analytical HPLC Ret. time: 6.16 min (Condition H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[C:6]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[C:5]2[Cl:22].[CH3:23][O-:24].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:24][CH3:23])[C:6]([CH2:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=[C:5]2[Cl:22]
Reactant: C[O-]
Reactant: N#Cc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C#N)cc1
Temperature: 105 °C
Reaction time: 9 h

Procedure:
A heterogeneous mixture of 4-((6-bromo-2,4-dichloroquinolin-3-yl)methyl)benzonitrile (650 mg, 1.16 mmol, Intermediate 44: step c) and sodium methoxide (314 mg, 5.81 mmol) in dry toluene (2.2 mL) was heated at 105° C. After 9 hours, the mixture was cooled to ambient temperature and filtered through Celite®, rinsing with DCM. The filtrate was concentrated and the crude was purified by flash column chromatography (silica gel, 0-5% EtOAc-Hexanes) to provide the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:33][O-:34].[Na+].O>CO>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[O:34][CH3:33])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: C[O-]
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
A solution of 2-chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (50 mg, 0.10 mmol) in methanol (5 ml) was treated with sodium methoxide (11 mg, 0.20 mmol) and the mixture was allowed to stir at ambient temperature for 1 hour then heated under reflux for 4 hours. Water (1 ml) was added and the solvent evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and the layers separated using a 5 micron PTFE frit and the filtrate was evaporated. The residue was purified by preparative plate chromatography on silica eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a colourless oil (47 mg, 95%). 1H NMR δ (ppm)(CDCl3): 8.67 (1H, d, J=7.6 Hz), 7.92 (1H, s), 7.44 (1H, d, J=7.6 Hz), 4.15 (3H, s), 3.65 (2H, d, J=6.1 Hz), 2.94-2.89 (3H, m), 2.07-1.84 (6H, m), 1.40-1.32 (2H, m), 1.25-1.15 (3H, m), 0.78-0.70 (3H, m), 0.57-0.53 (2H, m), 0.42 (2H, q, J=5.3 Hz), 0.07 (2H, q, J=5.0 Hz). MS (m/e)=489.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2SC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][OH:24].O>CO>[C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[O:24][CH3:23])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Reactant: CO
Solvent: O
Product: COc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Temperature: 90 °C

Procedure:
3-Benzenesulfonyl-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine (50 mg, 0.15 mmol) was dissolved in methanol (2 ml) and heated at 90° C. for 4 days. When the conversion reached about 50% the product was isolated from the starting material by preparative HPLC (XTerra™ MS C18 5.0 mM, MeOH/H2O as the eluent) to yield 21 mg of bright yellow product.