Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)OCC[O:3]1.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O.C(OCC)C>[C:7]1([CH:2]([OH:3])[CH3:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1(c2ccccc2)OCCO1
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Solvent: CCOCC
Solvent: O
Product: CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 90 %

Procedure:
2-Methyl-2-phenyl-1,3-dioxolane (0.5 g, 3 mmol), sodium dodecyl sulfate (0.2 g, 0.7 mmol) and a stir bar were added to the inside of a PDMS thimble. p-Toluene sulfonic acid monohydrate (0.145 g, 0.8 mmol) was dissolved in 4 mL water and added to the inside of the PDMS thimble followed by 2 mL of hexanes. LiAlH4 (0.145 g, 3.8 mmol) was added to the outside of the PDMS thimble with 5 mL hexanes. The reaction was stirred at 25° C. for 19 hours. Water (5 mL) was added. The PDMS thimble was swelled with 20 mL hexanes and 2×20 mL diethyl ether. The organics were combined and dried over MgSO4. The product was purified by column chromatography eluting with 1:4 ethyl acetate:hexanes to yield a colorless liquid (0.33 g, 89% yield). 1H NMR (CDCl3): δ 1.44 (d, J=6.9 Hz, 3H), 2.42 (s, 1H), 4.81 (q, J=6.9 Hz, 1H), 7.22-7.33 (m, 5H). 13C NMR (CDCl3): δ 25.05, 70.22, 125.31, 127.32, 128.37, 145.74.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][O:26][C:27]1[CH:41]=[CH:40][C:30]([CH2:31][N:32]2[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][C:33]2=[O:39])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:34]4[C:35]([CH3:38])([CH3:37])[CH2:36][N:32]([CH2:31][C:30]5[CH:40]=[CH:41][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[C:33]4=[O:39])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Reactant: COc1ccc(CN2CC(C)(C)NC2=O)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(CN2CC(C)(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)c(C)c3)C2=O)cc1

Procedure:
To a mixture of (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (155 mg) described in Preparation Example 118, 1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one (112 mg) described in Preparation Example 54, cesium carbonate (261 mg) and copper(I) iodide (76 mg) were added toluene (10 mL) and N,N′-dimethylethylenediamine (86 μL), and the mixture was stirred with heating under reflux for 19 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one. The obtained 3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-methylphenyl}-1-(4-methoxybenzyl)-4,4-dimethylimidazolidin-2-one was dissolved in trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 22 hr. The solvent was evaporated from the reaction mixture, and 5% aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform/methanol (10:1). The organic layer was dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:methanol) to give the title compound (74 mg).
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].[NH2:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]([OH:17])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]>C(OCC)C.C(OCC)(=O)C>[CH2:29]([O:28][C:26]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:10]([OH:17])[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)OC(=O)C(O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)OC(=O)C(O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Water (10 ml) and sodium carbonate (763 mg) are added to a solution of isopropyl (2RS,3S)-3-amino-2-hydroxy-4-phenylbutyrate (800 mg, Reference compound No. 4-1) in diethyl ether (10 ml). Benzyl chloroformate (691 mg) is added to the mixture, and the whole is stirred for two hours. Ethyl acetate is added to the reaction mixture, and the whole is washed with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine successively and dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (1.02 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].[Cl:14][C:15](Cl)([Cl:19])[CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]([Cl:19])=[CH:16][CH2:17][O:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][OH:11])=[C:6]([Cl:12])[CH:5]=1
Reactant: OCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step C, by the reaction of 10.0 grams (0.045 mole) of 3,5-dichloro-4-(2-hydroxyethoxy)phenol, 12.0 grams (0.066 mole) of 1,1,1,3-tetrachloropropane and 12.0 grams (0.086 mole) of potassium carbonate in 100 mL of DMF. The reaction mixture was warmed to 50° C. where it stirred during an 18 hour period, then it was warmed to 70° C. where it stirred during an additional five hour period. After this time the reaction mixture was cooled, water was added, and the mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:4 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 10.9 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:6])[C:4]#[N:5].[CH3:7][O:8][P:9]([CH2:13][CH2:14][OH:15])(=[O:12])[O:10][CH3:11].C(N(CC)CC)C>C1COCC1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:7][O:8][P:9]([CH2:13][CH2:14][O:15][CH2:2][C:3](=[CH2:6])[C:4]#[N:5])([O:10][CH3:11])=[O:12]
Reactant: COP(=O)(CCO)OC
Reactant: C=C(C#N)CCl
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C#N)COCCP(=O)(OC)OC
Temperature: 65 °C
Yield: 54.2 %

Procedure:
86.3 g (850 mmol) 2-(chloromethyl)-acrylonitrile are added dropwise at room temperature to a solution of 130.9 g (850 mmol) 2-hydroxyethylphosphonic acid dimethylester, 85.9 g (850 mmol) triethylamine (TEA) and 40 mg phenothiazine (stabilizer) in 1 l THF. Subsequently, the mixture is heated for 6 hours at 65° C. under reflux. 9.1 g (90 mmol) TEA and 9.1 g (90 mmol) 2-(chloromethyl)-acrylonitrile are once again added one after the other and the mixture is heated for a further 24 hours under reflux. After the reaction mixture has cooled, the formed deposit of TEA hydrochloride is filtered out and is washed twice with 50 ml THF. After the THF phases have been concentrated on the rotary evaporator, the residual raw product is taken up in 650 ml methylene chloride and washed twice with water. After it has been dried over anhydrous sodium sulphate, the mixture is concentrated and the residual liquid undergoes fractional distillation in the fine vacuum. 101.0 g (54% yield) of a colourless liquid results at b.p. 150° C. (0.05 mbar).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:30]1[CH:31]=[N:32][C:33]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[N:34][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:40][C:39]1[CH:38]=[CH:37][C:36]([C:33]2[N:32]=[CH:31][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][N:34]=2)=[CH:43][CH:42]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCc1cnc(-c2ccc(C=O)cc2)nc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCc1cnc(-c2ccc(C=C(Br)Br)cc2)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.5 %

Procedure:
A solution of 5.44 g of tetrabromomethane in 80 ml of methylene chloride was placed at 0° C. under argon gasification in a sulphonation flask equipped with a mechanical stirrer and treated within 10 minutes with a solution of 8.6 g of triphenylphosphine in 20 ml of methylene chloride. After completion of the addition, the clear orange solution was stirred at 0° C. for a further 5 minutes and then a solution of 2.08 g of p-(5-pentyl-2-pyrimidinyl)benzaldehyde in 15 ml of methylene chloride was added dropwise within 5 minutes. The mixture was subsequently stirred at 0° C. for a further 30 minutes, then the flask content was poured into 700 ml of hexane and the precipitate which thereby separated was filtered off (rinsing with hexane). The concentrated filtrate was digested with 200 ml of hexane, left to stand at 0° C. for 18 hours, filtered (rinsing with hexane) and the filtrate was concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.7 g) on silica gel with 3% ethyl acetate/petroleum ether gave 2.70 g (80%) of 2-[p-(2,2-dibromovinyl)phenyl]-5-pentylpyrimidine as colourless crystals (purity 94.5%); m.p. 74° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH:25]1([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[C:34]([F:47])[CH:33]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29](=[O:30])[NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@H:19]4[CH3:24])[C:5]4[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=4[N:7]=3)=[C:34]([F:47])[CH:33]=2)[CH2:26][CH2:27]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(C(=O)OC(C)(C)C)C2
Yield: 78 %

Procedure:
Method as described for example 147 using (R)-tert-butyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (from step 1) and 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) as starting materials. Reaction solvent was removed in vacuo. The residue was then partitioned between DCM (100 ml) and water (80 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by flash chromatography using 20-100% ethyl acetate/petroleum ether 40-60 to yield an off white solid (1.107 g, 2.16 mmol, 78%).
Reaction SMILES: O1C=CC=C1C=O.[OH-].[K+].[N+](C[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=O)#[C-].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C@@H:25]1[O:29][CH:28]=[N:27][C@H:26]1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]>CO>[CH:16]1[C:17]2[C:22](=[CH:23][CH:24]=[CH:19][CH:18]=2)[C:21]([C@@H:25]2[O:29][CH:28]=[N:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:13][N:15]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C@@H:25]1[O:29][CH:28]=[N:27][C@H:26]1[C:30]([N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:31]
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: O=C([C@@H]1N=CO[C@H]1c1ccco1)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=Cc1ccco1
Product: O=C([C@@H]1N=CO[C@H]1c1cncc2ccccc12)N1CCCC1

Procedure:
BLE 04136C was prepared in accordance with method D using 2-furaldehyde (0.449 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue was purified by column chromatography on silica (cyclohexane:EtOAc=100:0 to 0:100) to led, after evaporation, to trans-(5-(furan-2-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04136D as a yellow pale oil (0.742 g, 58.5% yield).
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].[C:7]1(C)[CH:12]=[CH:11][C:10]([CH:13]2[CH:18]=[CH:17][N:16](C(=O)C(C)(C)C)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[Mn]([O-])(=O)(=O)=O.[K+].[Mn]([O-])(=O)(=O)=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:11][CH:12]=1)([OH:2])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C2C=CN(C(=O)C(C)(C)C)CC2)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Product: O=C(O)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1.0 g of anhydrous sodium carbonate, 0.05 g of benzyltributylammonium chloride and 0.8 g of 4-p-tolyl-N-pivaloyldihydropyridine are added at room temperature to 75 ml of a 2% strength by weight aqueous potassium permanganate solution. After stirring at 100° C. for 1.5 hours, excess permanganate is reduced by means of sodium dithionite, the precipitated manganese dioxide is filtered off, the filtrate is acidified and the precipitated product is filtered off to give 4-(4′-carboxyphenyl)-pyridine in a yield of 81%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)[N:8]=1)(=O)=O.[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([Cl:35])[C:26]=1[NH2:36]>O1CCOCC1>[Cl:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[C:27]([Cl:35])[C:26]=1[NH:36][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=2)[N:8]=1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#Cc1ccc(Nc2nccc(OS(=O)(=O)C(F)(F)F)n2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(Nc2nccc(Nc3c(Cl)cc(C(F)(F)F)cc3Cl)n2)cc1
Temperature: 170 °C
Yield: 9.2 %

Procedure:
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.003 mol), 2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1 M HCl in diethyl ether (4.5 ml) in 1,4-dioxane (10 ml) were combined in a tube and heated under Ar until all diethyl ether had evaporated. The tube was sealed and heated at 170° C. for 2.5 days. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH:NH4OH 100:0:0 to 99:0.9:0.1). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from acetonitrile, filtered off and dried, yielding 0.22 g (15.9%) of 4-[[4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (compound 61). b) 4-[[4-[(4-chloro-5-methyl-2-pyrimidinyl]amino]benzonitrile (0.01541 mol), 4-amino-3,5-dimethyl-benzonitrile (0.00219 mol), 1-methyl-2-pyrrolidinone (4 ml), 1,4-dioxane (15 ml) and diisopropylethylamine (0.0154 mol) were combined in a flask under a stream of argon and heated at 160-230° C. for 16 hours. CH2Cl2 and 1N NaOH were added, and the mixture was stirred 1 hour and filtered to give a brown solid (*). The CH2Cl2 filtrate was separated and was evaporated and purified by flash column chromatography (eluent: 2% CH3OH/CH2Cl2). The desired fractions were combined, evaporated and the residue was stirred in CH2Cl2. The solid precipitate was filtered off, combined with the brown solid (*) and recrystallized from CH3CN. The precipitate was filtered off and dried, yielding 1.57 g (29%) of 4-[[2-[(4-cyanophenyl)amino]-5-methyl-4-pyrimidinyl]amino]-3,5-dimethylbenzonitrile (compound 89). c) 2-[(4-cyanophenyl)amino]-4-pyrimidinyl trifluoromethanesulfonate (0.0022 mol) and 2,6-dichloro-4-(trifluoromethyl)-benzenamine (0.0044 mol) were combined in 1,4-dioxane (2.5 ml) and heated in a sealed tube under Ar at 170° C. for 40 hours. The reaction mixture was allowed to cool to room temperature. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2C2:CH3OH:NH4OH 100:0:0 to 97:2.7:0.3). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from CH3CN, filtered off and dried, yielding 0.086 g (9.2%) of 4-[[4-[[2,6-dichloro-4-(trifluoromethyl)-phenyl]amino]-2-pyrimidinyl]amino]benzonitrile (compound 66).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:21])[C:5]2[C:6]([F:20])=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:30]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:31]=2[CH:32]=[CH:33][NH:34]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:20][C:6]1[C:5]2[C:4]([NH2:21])=[CH:3][C:2]([C:30]3[CH:38]=[CH:37][CH:36]=[C:35]4[C:31]=3[CH:32]=[CH:33][NH:34]4)=[CH:10][C:9]=2[N:8]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:7]=1
Reactant: Nc1cc(Br)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2c1c(F)nn2S(=O)(=O)c1ccccc1
Temperature: 110 °C

Procedure:
6-Bromo-3-fluoro-1-(phenylsulfonyl)-1H-indazol-4-amine (350 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (230 mg), potassium phosphate (601 mg) and Pd(dppf)Cl2 (69 mg) were placed in a microwave vial with 1,4-dioxane (5 ml) and water (2.5 ml) and the mixture heated at 110° C. for 30 min. After this time the mixture was partitioned between water (200 ml) and DCM (200 ml) and the DCM layer was collected. The aq layer was extracted with DCM (100 ml) and the combined organic layers dried using a hydrophobic frit and the solvent was removed in vacuo. The residue was adsorbed onto silica gel and purified using chromatography on silica gel eluting with 0-100% ethyl acetate in cyclohexane to give the title compound, 350 mg.
Reaction SMILES: Cl.[CH3:2][NH:3][C@@H:4]([CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]([F:22])([F:21])[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[F:13][C:14]([F:22])([F:21])[CH2:15][CH2:16][S:17]([N:3]([C@@H:4]([CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:2])(=[O:19])=[O:18]
Reactant: C=CCC[C@H](NC)C(=O)OC
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Agent: Cl
Product: C=CCC[C@@H](C(=O)OC)N(C)S(=O)(=O)CCC(F)(F)F
Yield: 56 %

Procedure:
Step M (1): Same procedure as Step I (1). (S)-Methyl 2-(methylamino)hex-5-enoate hydrochloride from Step K (2) was sulfonylated with 3,3,3-trifluoropropane-1-sulfonyl chloride according to the procedure outlined in Step I (1). The procedure provided 242 mg (56% yield) of (S)-methyl 2-(3,3,3-trifluoro-N-methylpropylsulfonamido)hex-5-enoate. LC-MS (M+H)+=318.3; 1H NMR (500 MHz, CDCl3) δ ppm 1.73-1.85 (m, 1H) 2.02-2.21 (m, 3H) 2.59-2.73 (m, 2H) 2.87 (s, 3H) 3.16-3.32 (m, 2H) 3.76 (s, 3H) 4.55 (dd, J=10.68, 4.58 Hz, 1H) 4.99-5.14 (m, 2H) 5.74-5.87 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:8].C(N(CC)CC)C.[Cl:39][S:40]([C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46](Cl)=[O:47])(=[O:42])=[O:41]>ClCCl>[Cl:39][S:40]([C:43]1[CH:44]=[C:45]([CH:49]=[CH:50][CH:51]=1)[C:46]([NH:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:8])=[O:47])(=[O:42])=[O:41]
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Cl)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
A mixture of 43.0 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 14.0 mL of triethylamine, and 215 mL of dichloromethane was added dropwise to a mixture of 24.8 g of 3-(chlorosulfonyl)benzoyl chloride and 430 mL of dichloromethane under ice-cooling, followed by stirring for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was washed with ethanol to obtain 59.5 g of methyl 4-[2-(4-{[(2-{[3-(chlorosulfonyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate as a yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[C:19]([C:22]([OH:24])=O)[CH:18]=2)=[CH:13][CH:12]=1.FC1C=CC(C(=O)C)=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:58][CH2:59][C:60]([N:62]1[CH2:67][CH2:66][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=2)[CH2:64][CH2:63]1)=[O:61]>CN(C=O)C.O>[O:61]=[C:60]([N:62]1[CH2:63][CH2:64][CH:65]([O:68][C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:76])[F:77])[CH:70]=2)[CH2:66][CH2:67]1)[CH2:59][NH:58][C:22]([C:19]1[CH:18]=[C:17]([C:14]2[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=2)[O:21][N:20]=1)=[O:24]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2)on1
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccc(F)cc2)on1
Reaction time: 8 h
Yield: 54 %

Procedure:
DIPEA (131 mg, 1.0 mmol) was added to a stirred solution of 5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid (60 mg, 0.29 mmol) (prepared by the method used for the synthesis of Intermediate 25, starting from 4′-fluoroacetophenone) in DMF (2 mL) followed by HOBt (41 mg, 0.3 mmol) and EDCI.HCl (58 mg, 0.3 mmol). After 2 minutes 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (125 mg, 0.37 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Purification by recrystallisation from chloroform afforded 77 mg (54.2% Yield) of 5-(4-fluoro-phenyl)-isoxazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 492, 96.7%. 1H NMR (300 MHz, DMSO-d6): δ8.62 (t, 1H), 8.0 (m, 2H), 7.5 (t, 1H), 7.38 (m, 3H), 7.26 (t, 3H), 4.8 (m, 1H), 4.2 (d, 2H), 3.7 (m, 4H), 3.4 (m, 2H), 2.0 (m, 2H), 1.6 (m, 2H).