Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].FC(F)(F)S(O)(=O)=[O:17].ClC1C=C(C=CC=1)C(OO)=O.C1(=O)C2C(=CC=CC=2)CC1>ClCCl.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10](=[O:13])[O:17]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Reactant: O=S(=O)(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C1CCc2ccccc21
Agent: O=S([O-])OS(=O)[O-]
Solvent: ClCCl
Product: O=C1CCc2ccc([N+](=O)[O-])cc2O1

Procedure:
6-Nitroindanone [J. Med. Chem., 19, 1976, 472–475] (900 mg, 5.0 mmol) was suspended in dichloromethane (25 ml) and trifluoromethanesulphonic acid (0.05 ml) added. The resulting solution was cooled on ice. In a second flask, m-chloroperoxybenzoic acid [55%, Aldrich] (10 g) was suspended in dichloromethane and stirred for several minutes. The insoluble material was removed by filtration through a hydrophobic membrane and the filtrate evaporated to give a white powder. A portion of this material (2.6 g) was added portionwise to the indanone and the resultant suspension stirred for 72 h at room temperature. The reaction mixture was diluted with dichloromethane (10 ml) and aqueous sodium disulphite (20%; 10 ml). The aqueous layer was extracted (30 ml×3) with dichloromethane and the combined organic layers washed with saturated aqueous sodium bicarbonate (20 ml), brine (10 ml), and dried (MgSO4) to yield crude 7-nitro-chroman-2-one as a brown solid (1.1 g, ˜70% pure);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH2:12][SH:13])=[CH:4][N:3]=1.[N+:14]([CH:17]=[C:18](SC)SC)([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][S:13][C:18]2=[CH:17][N+:14]([O-:16])=[O:15])=[CH:4][N:3]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: SCCCNCc1ccc(Cl)nc1
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCCN1Cc1ccc(Cl)nc1
Yield: 22.9 %

Procedure:
A mixture of N-(2-chloro-5-pyridylmethyl)3-aminopropanethiol (4.3 g), 1-nitro-2,2-bis(methylthio)ethylene (3.3 g) and ethanol (40 ml) was heated under reflux for 10 hours in a stream of nitrogen. After the reaction, about 2/3 of ethanol was distilled off under reduced pressure. Ether was added little by little to the reaction mixture to precipitate crystals. The crystals were collected by filtration, and washed with a mixture of ethanol and ether to give the desired 3-(2-chloro-5-pyridylmethyl)-2-nitromethylenetetrahydro-2H-1,3-thiazine (1.3 g) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][S:6][CH2:5][S:4][CH2:3]1.CCCCCC.C([Li])CCC.[CH3:19][Si:20](Cl)([CH3:22])[CH3:21]>O1CCCC1>[CH3:19][Si:20]([CH3:22])([CH3:21])[CH:5]1[S:6][CH2:7][N:2]([CH3:1])[CH2:3][S:4]1
Reactant: C[Si](C)(C)Cl
Reactant: CN1CSCSC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CSC([Si](C)(C)C)SC1

Procedure:
5-Methyl-1,3,5-dithiazine, 2.7 g, was dissolved in 20 ml of tetrahydrofuran and 14 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added to the solution in an argon flow at -73° C. The mixture was stirred at the same temperature for an hour. Then, 2.4 g of trimethylsilyl chloride was dropwise added to the mixture at the same temperature. After completion of the dropwise addition, the temperature of the reaction mixture was gradually elevated to 0° C. and then stirred for 90 minutes to give crude 2-trimethylsilyl-5-methyl-1,3,5-dithiazine. Without purifying the crude product, 14 ml of 1.6 mole hexane solution of n-butyl lithium was dropwise added thereto at -10° C. followed by stirring for 30 minutes. After cooling to -73° C., a solution of 4.5 g of 4-phenoxypropiophenone in 10 ml of tetrahydrofuran was dropwise added. After completion of the dropwise addition, the temperature was gradually elevated to room temperature followed by stirring for 14 hours. After saturated sodium chloride aqueous solution was added to the mixture, it was extracted with chloroform. After drying the chloroform phase over magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform : hexane =2 : 1) to give 5.5 g of the product.
Reaction SMILES: C([O:8][C:9](=[O:25])[C@H:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[NH:11][C:12]([N:14]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>CO.[Pd]>[N:14]1([C:12]([NH:11][C@H:10]([C:9]([OH:25])=[O:8])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Yield: 92.7 %

Procedure:
The compound obtained in (1) (1.75 g) was dissolved in methanol (30 ml). 10% Pd-C (0.30 g) was added and the mixture was stirred vigorously at room temperature under atmospheric pressure of hydrogen for 1.5 h. The catalyst was filtered off and the filtrate was concentrated to give the product (1.2 g) as a colorless foam.
Reaction SMILES: [CH3:1][C:2]1[C:22](=O)[C:20](=[O:21])[C:5]2[C@@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C@@:7]3([O:13][CH3:14])[C@H:11]4[NH:12][C@H:10]4[CH2:9][N:8]3[C:4]=2[C:3]=1[OH:24].CO.P(=O)(O)(O)O.[N+:32](=C(C1C=CC=CC=1)C1C=CC=CC=1)=[N-]>C(Cl)Cl.O>[CH3:1][C:2]1[C:3](=[O:24])[C:4]2[N:8]3[C@@:7]([O:13][CH3:14])([C@H:6]([CH2:15][O:16][C:17]([NH2:19])=[O:18])[C:5]=2[C:20](=[O:21])[C:22]=1[NH2:32])[C@H:11]1[NH:12][C@H:10]1[CH2:9]3
Reactant: CO[C@@]12[C@H](COC(N)=O)C3=C(C(O)=C(C)C(=O)C3=O)N1C[C@@H]1N[C@@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: O=P(O)(O)O
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CO[C@@]12[C@H](COC(N)=O)C3=C(C(=O)C(C)=C(N)C3=O)N1C[C@@H]1N[C@@H]12
Reaction time: 15 h

Procedure:
We turn now to the case where drying (i.e., water removal) is not carried out, i.e., in the case where aqueous solution of basic 7-salt oxide-9a-methoxymitosane is treated directly with acid. The acid is preferably aqueous phosphoric acid and is admixed to provide a pH of 4.7 to 6.5, very preferably from 5 to 6, to produce aqueous solution of 7-hydroxy-9a-methoxymitosane. The reaction of this with diazodiphenylmethane proceeds as follows. The diazodiphenylmethane is admixed. The solvent in which the diazodiphenylmethane is dissolved and/or which is otherwise admixed is a solvent or solvent combination in which both the 7-hydroxy-9a-methoxymitosane and diazodiphenylmethane are soluble and preferably is the combination of methylene chloride and methanol in a volume ratio of methylene chloride to methanol ranging, for example, from 0.5:1 to 3:1. The reaction between 7-hydroxy-9a-methoxymitosane proceeds despite the presence of water apparently as an extractive alkylation where the organic solvent extracts the 7-hydroxy-9a-methoxymitosane from the water phase for reaction in organic solvent phase (preferably methylene chloride). The alkylation reaction to produce 7-(diphenylmethyl)oxy-9a-methoxymitosane proceeds, for example, at a temperature ranging from 0° C. to 30° C. for 1 to 10 hours using an excess of diazodiphenylmethane, e.g., 2 to 5 equivalents of diazodiphenylmethane. During the alkylation reaction, acid, preferably aqueous phosphoric acid, is preferably added periodically as may be necessary to maintain the pH in the range of 4.7 to 6.5, very preferably 5 to 6. When the alkylation reaction is completed, organic phase is separated and substantially pure 7-(diphenylmethyl)oxy-9a-methoxymitosane is recovered, e.g., by drying to remove water and evaporating to remove organic solvent and recovering product from the residue by chromatography on Al2O3 or SiO2. Additional product can be obtained by vigorously mixing the aqueous phase with diazodiphenylmethane in solvent for it and 7 -hydroxy-9a-methoxymitosane, preferably methylene chloride, and reacting, preferably at 15° C. to 25° C. for 10 to 20 hours, and recovering additional product, e.g., by chromatography. Yields from mitomycin C, including product obtained from workup of the aqueous phase, of 40 to 60% have been obtained. These yields are unexpected in view of the Sami, et al article referred to above.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:22][CH:23]([CH3:50])[C:24]([C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)=[O:25].[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:25][C:24]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1)([C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)[CH:23]([CH3:50])[CH3:22]
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CN1Cc2c(ccc3cc(Br)ccc23)C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -70 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
7-Bromo-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.14 g) was suspended in THF (6 mL) and dissolved by heating. This solution was cooled to −70° C. and a solution (1.6 M: 0.75 mL) of n-butyllithium in hexane was slowly added dropwise. After stirring for 1 hr., a solution (1 mL) of 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanone (0.16 g) in THF was added dropwise. After stirring at −70° C. for 30 min., 20% aqueous ammonium chloride was added to stop the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: hexane-ethyl acetate, 1:1—ethyl acetate) to give the title compound (0.13 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[C:22]2[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C@H:32]4[CH2:31][CH2:30][C@@H:29]([C:22]5[C:21]6[C:25](=[CH:26][CH:27]=[C:19]([F:18])[CH:20]=6)[N:24]([CH3:28])[CH:23]=5)[CH2:34][CH2:33]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Brc1cc(N2CCNCC2)c2ncccc2c1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(F)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cn1cc([C@H]2CC[C@@H](N3CCN(c4cc(Br)cc5cccnc45)CC3)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromo-8-piperazin-1-yl-quinoline (610 mg, 2.09 mmol), 4-(5-fluoro-1-methyl-1H-indol-3-yl)-cyclohexanone (510 mg, 2.09 mmol), and sodium triacetoxyborohydride (660 mg, 3.14 mmol) in dichloroethane (40 mL) was added acetic acid (0.24 mL, 4.18 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (50 mL) and H2O (100 mL) then extracted in CH2Cl2 (100 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc). The majority of the cis compound precipitated out of 5% MeOH/EtOAc before application to the column and was purified by filtration affording 510 mg (47%) of the cis isomer as a pale yellow solid: mp 215-217° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:12](Cl)(=[O:22])/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)(=O)/C=C/CCCCCCC.S(Cl)(Cl)=O>O1CCCC1>[C:12]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:22])/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C1CCNC1
Reactant: CCCCCCC/C=C/C(=O)Cl
Agent: CCCCCCC/C=C/C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCC/C=C/C(=O)N1CCCC1
Yield: 62.7 %

Procedure:
A tetrahydrofuran solution (20 mL) of pyrrolidine (0.71 g, 0.01 mol) containing pyridine (0.79 g, 0.01 mol) was added to a tetrahydrofuran solution (20 mL) of (E)-2-decenoic acid chloride (1.9 g, 0.01 mol), synthesized using (E)-2-decenoic acid and thionyl chloride, and the mixture was heated under refluxing in a warm water bath for 3 hours. After distilling off excess tetrahydrofuran, water was added to a liquid reaction mixture, and the liquid mixture was extracted with ethyl acetate, and washed with water, and ethyl acetate was distilled off. The residue was purified with silica gel column chromatography (developing solvent:hexane:ethyl acetate=1:3), to give an intended compound (1.4 g) in the form of a colorless oily substance.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.[OH-].[Na+].[N+]([O-])([O-])=O.[Ag+:32]>C(O)CCC>[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:32]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Reaction time: 0.92 h

Procedure:
While stirring 43.8 g of behenic acid (manufactured by Henkel Co., trade name: Edenor C22-85R), 730 ml of distilled water, and 60 ml of butanol at 79° C., 117 ml of 1 N NaOH aqueous solution was added thereto over 55 minutes and the mixture was allowed to reaction for 240 minutes. Then, 112.5 ml of an aqueous solution containing 19.2 g of silver nitrate was added thereto over 45 seconds and the solution was allowed to stand for 20 minutes, and then the temperature was lowered to 30° C. The solid content was then filtered by suction. The solid content was washed with water until the conductivity of the filtrate reached 30 mS/cm. The thus-obtained solid content was not dried and treated as a wet cake. Seven point four (7.4) grams of polyvinyl alcohol (trade name: PVA-205) and water were added to the wet cake of the amount corresponding to 100 g of dried solid content to make the entire amount 385 g, and then preliminarily dispersed in a homomixer. The preliminarily dispersed starting solution was treated three times using a disperser (trade name: Micro-fluidizer M-110S-EH equipped with G10Z interaction chamber, manufactured by Micro Fluidex International Corp.). Pressure of the disperser was adjusted to 1,750 kg/cm2. Thus, silver behenate dispersion B was obtained. Silver behenate grains contained in the thus-obtained silver behenate dispersion were acicular grains having an average short axis length of 0.04 μm, average long axis length of 0.8 μm, and variation coefficient of 30%. Grain size was measured by Master Sizer X (manufactured by Malvern Instruments Ltd.). Coiled heat exchangers were respectively installed before and after the interaction chamber. The desired temperature of dispersion was set by adjusting the temperature of the cooling medium.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:19][C@@H:18]([OH:20])[C@H:17]([CH3:21])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:20][C@H:18]1[C@H:17]([CH3:21])[CH2:16][CH2:15][C@@H:14]([NH:13][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:19]1
Reactant: C[C@@H]1CC[C@@H](N)C[C@H]1O
Reactant: CSc1ncc(C#N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C#N)c(N[C@@H]2CC[C@@H](C)[C@H](O)C2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a stirring solution of 4-chloro-2-(methylthio)-pyrimidine-5-carbonitrile (310 mg, 1.670 mmol) and (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (304 mg, 1.837 mmol; synthesis described herein) in DMF (2.4 mL) was added DIEA (0.873 ml. 5.01 mmol). The resulting mixture was stirred at 60° C. for 2 h. LCMS showed the reaction to be complete. The solvent was evaporated under reduced pressure and the residue diluted with 150 mL ethyl acetate and 50 mL water. The layers were separated and the aqueous phase was extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with brine (2×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil that solidified upon standing to afford 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylthio)pyrimidine-5-carbonitrile (418 mg, 1.503 mmol, 90% yield). MS (ESI) m/z 279.3 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24]C(=O)C(C)(C)C)[CH2:20][CH2:19]2)[CH3:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@@H:16]([N:18]2[CH2:19][CH2:20][CH:21]([OH:24])[CH2:22][CH2:23]2)[CH3:17])[CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](CN1CCC(NC(=O)OC(C)(C)C)CC1)N1CCC(OC(=O)C(C)(C)C)CC1
Agent: C[O-]
Agent: [Na+]
Product: C[C@@H](CN1CCC(NC(=O)OC(C)(C)C)CC1)N1CCC(O)CC1

Procedure:
Ester 54 from above (1.7 g, 3.52 mmol) is treated with NaOMe (0.5M in methanol, 21 ml, 10.5 mmol) and heated under reflux for 24 hours. The solvent is then evaporated, the residue taken up in DCM and extracted with 1N-NaOH and brine. After drying and evaporation the crued is purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 1% to 3%) to give a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(=[CH:47][C:48]([O:50][CH3:51])=[O:49])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=[CH:47][C:48]([O:50][CH3:51])=[O:49])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 3.08 g (7.5 mmol) of 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanal in 40 mL chloroform is added 2.88 g (8.4 mmol) of methyl (triphenylphosphoranylidene)-acetate and then subjected to reflux for 3 hours. The solvent is evaporated and the residue taken up in ether and extracted with 0.5N HCl (3×20 mL). The aqueous extracts are combined and washed with ether. The aqueous phase is adjusted to pH 8 and then extracted with methylene chloride (3×50 mL). Combined organic extracts are dried (MgSO4), filtered and then evaporated to give an amber oil. This is purified by flash chromatography using 7:3 EtOAc: hexane as the eluent to give methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-oct-2-enoate as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:15][CH:14]=2)[N:3]=1.CCN(CC)CC.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45]([O:47][CH3:48])=[O:46])#[CH:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:24]([O:23][C:22]([NH:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:37]#[C:36][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)[CH3:20])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate (A63) (487 mg, 1.17 mmol), Et3N (760 μL), methyl 2-(2-ethynylphenyl)acetate (K1) (244 mg, 1.40 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), CuI (22.0 mg, 0.117 mmol) and PPh3 (36.0 mg, 0.117 mmol) in DMF (4.6 mL) was heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated in vacuo and the residue purified by silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-25% EtOAc in cyclohexane) to give the title compound A64 as a yellow solid (400 mg, 62%); 1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 7.70 (dd, J=7.83, 1.17 Hz, 1H), 7.61 (d, J=8.61 Hz, 2H), 7.43 (m, 3H), 7.34 (d, J=8.40 Hz, 2H), 4.78 (m, 2H), 3.98 (s, 2H), 3.73 (s, 3H), 1.61 (s, 1H, peak obscured), 1.46 (m, 12H). LCMS-B: rt 8.90 min; m/z 555 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:19]([NH2:21])=[O:20])[C:15]([F:18])=[CH:16][CH:17]=3)=[N:7][C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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.O>[F:22][C:13]1[C:12]([O:11][CH2:10][C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[CH:23][C:6]=3[N:7]=2)=[CH:17][CH:16]=[C:15]([F:18])[C:14]=1[C:19]([NH2:21])=[O:20]
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Reactant: OB(O)c1ccncc1
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: C1COCCO1
Product: NC(=O)c1c(F)ccc(OCc2nc3cc(-c4ccncc4)ccc3s2)c1F
Temperature: 25 °C
Yield: 28 %

Procedure:
A mixture of 3-[(5-bromo-1,3-benzothiazol-2-yl)methoxy]-2,6-difluorobenzenecarboxamide (168 mg, 0.42 mmol, 1 equiv.), 4-pyridine boronic acid (98 mg, 0.63 mmol, 1.5 equiv.) and 2M aqueous Na2CO3 solution (0.42 ml, 0.82 mmol, 2 equiv.) were suspended in dioxane (3.5 ml) and the mixture was degassed and flushed with N2. Tetrakis(triphenylphosphine)palladium(0) catalyst (37 mg, 0.031 mmol, 0.075 equiv.) was added and the reaction mixture was heated under reflux for 12 h. After cooling at r.t., the mixture was diluted with H2O and the precipitant solid was filtered and rinsed with H2O, IMS, IMS/Et2O and Et2O. Re-crystallised from CH3CN, to give the desired product as an off-white solid, 47 mg (28% yield), mp 255-258° C. HPLC-MS: m/z 398 [M+H]+, Rt=3.28 min.