Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][C:11]=2[F:19])[CH:6]=1)=[O:4].C(N(CC)CC)C>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C:16](=[O:18])[CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[F:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC(C)=O)c2c(F)ccc(Br)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC(C)=O)c2c(F)cccc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-acetoxy-8-bromo-5-fluoronaphthalene-2-carboxylic acid methyl ester (2.0 g) and triethylamine (0.72 g) in ethyl acetate (60 mL) was added palladium-carbon (600 mg) at room temperature, and the mixture was stirred for 1 hour at the same temperature under a hydrogen atmosphere. The insoluble material was removed by filtering through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(C)c1C(=O)O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1C(=O)Cl

Procedure:
To a mixture of 2,6-dimethylbenzoic acid (3 g; 0.02 mol) in toluene (50 ml) was added thionyl chloride (3.6 ml; 0.05 mol). The mixture thus obtained was refluxed for 2 hours. The solvent and the excess thionyl chloride were then evaporated off under reduced pressure. The residue thus obtained was taken up in toluene (50 ml) three times and evaporated under reduced pressure. The product thus obtained (3.6 g) was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]1([CH2:16]Br)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH:10]1([CH2:16][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrCC1CCCCC1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=Cc1ccc(OCC2CCCCC2)cc1

Procedure:
4-Hydroxybenzaldehyde (244 g) and 354 g of cyclohexylmethylbromide were added to 1 liter of methanol containing 414 g of anhydrous potassium carbonate (3.0M). The mixture was heated to reflux temperature overnight after which it was poured into cold water and extracted with ethyl acetate. The extracts were dried and evaporated in vacuo to yield the desired subtitled intermediate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH2:18])[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1.[CH3:19][N:20]([CH3:34])[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@@H:11]([NH:18][CH:24]2[CH2:23][CH2:22][C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([N:20]([CH3:34])[CH3:19])[CH2:26][CH2:25]2)[C:12]2[S:13][CH:14]=[C:15]([CH3:17])[N:16]=2)=[CH:2]1
Reactant: Cc1csc([C@H](N)Cc2c[nH]c3ccccc23)n1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1csc([C@@H](Cc2c[nH]c3ccccc23)NC2CCC(c3ccccc3)(N(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (R)-2-(1H-indol-3-yl)-1-(4-methylthiazol-2-yl)ethylamine (500 mg, 1.94 mmol) and 4-dimethylamino-4-phenylcyclohexanone (421 mg, 1.94 mmol) in anhydrous tetrahydrofuran (40 mL) was mixed with sodium sulphate (1.00 g) and stirred for 3 h at room temperature. After adding, acetic acid (291 mg, 287 μL, 4.85 mmol), sodium triacetoxyboron hydride (574 mg, 2.71 mmol) was added and the mixture stirred overnight at room temperature. The mixture was then filtered, the filtrate concentrated to low volume in a vacuum, the residue mixed with 1M potassium carbonate solution (50 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phases were dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (876 mg) was purified by flash chromatography (100 g, 20×4.0 cm) with ethyl acetate/methanol [95:5→9:1 and 1% ammonia in each case (33% in water)]. The non-polar diastereoisomer (450 mg) was purified once again by flash chromatography (38 g, 20×2.5 cm) with dichloromethane/methanol (300:9) and 1% ammonia (33% in water). The polar diastereoisomer (262 mg) was also purified once again by flash chromatography (18 g, 20×2.0 cm) with dichloromethane/methanol (24:1) and 1% ammonia (33% in water).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=1)=[O:6].[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28]([CH:30]3[CH2:32][CH2:31]3)=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:14][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: Cc1ccc(C(=O)CCCCl)cc1C
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C4CC4)c3)CC2)cc1C

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(3,4-dimethylphenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 419.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cncc(F)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-fluoropyridin-3-ylboronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 1 tR=1.5 min, m/z=453 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:16][CH:17]([C:19]([O:21]CC)=[O:20])[CH2:18][C:14]2=[CH:13][C:12]=1[CH3:24])=[O:10].[Cl-].[Na+]>CO.[OH-].[Na+]>[CH3:1][N:2]1[C:6]([S:7][CH3:8])=[CH:5][CH:4]=[C:3]1[C:9]([C:11]1[N:15]2[CH2:14][CH2:18][CH:17]([C:19]([OH:21])=[O:20])[C:16]2=[CH:24][C:12]=1[CH3:13])=[O:10]
Reactant: CCOC(=O)C1Cc2cc(C)c(C(=O)c3ccc(SC)n3C)n2C1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1ccc(C(=O)c2c(C)cc3n2CCC3C(=O)O)n1C
Yield: 97.9 %

Procedure:
A solution of (±)-ethyl 5-(1-methyl-5-methylthiopyrrol-2-oyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-2-carboxylate (0.50 g) in methanol (10 ml) and 10% sodium hydroxide (10 ml) were stirred at room temperature for 2 hours. A saturated sodium chloride solution was added to the solution and the methanol removed under reduced pressure. The aqueous solution was acidified with 3N hydrochloric acid with stirring and cooling and the resulting precipitate collected by filtration. The solids were washed with water, air dried, and recrystallized from ethyl acetate-hexane to give (±)-5-(1-methyl-5-methylthiopyrrol-2-oyl)-1,2-dihydro-6-methyl-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid (0.45 g, 98% yield) m.p. 182°-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][C:11]([OH:13])=O.[OH-].[Na+]>Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:8]=[C:9]([OH:14])[CH:10]=[C:11]2[OH:13]
Reactant: O=C(O)CC(=O)Nc1ccccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(O)c2cccc(Br)c2n1
Temperature: 140 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
N-(2-Bromophenyl)malonamic acid (43 g, 170 mmol), polyphosphoric acid (334 mL of 0.5 M), and hydrochloric acid (444 mL of 1 N) were combined and heated at 140° C. for three hours. The solution was allowed to cool to ambient temperature, and additional hydrochloric acid (603 mL of 1 N) was added. The reaction was stirred for four hours and then adjusted to pH 4 with the addition of 20% aqueous sodium hydroxide. A precipitate formed and was isolated by filtration, washed with water, and dried to provide 37.4 g of 8-bromoquinoline-2,4-diol as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:24]1([C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)O)[OH:25].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH3:22][S:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]2([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:23][C:31]3[CH:30]=[CH:29][CH:28]=[CH:26][C:24]=3[O:25]2)=[CH:20][CH:19]=1
Reactant: CSc1ccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Oc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CSc1ccc(C2(C3CCNCC3)Oc3ccccc3O2)cc1
Yield: 87.3 %

Procedure:
A solution of 4-(4-methylsulfanyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 28) (335 mg, 1.0 mmol), catechol (440 mg, 4.00 mmol) and p-TsOH.H2O (380 mg, 2.00 mmol) in xylene (10 mL) was heated at reflux under a Dean-Stark trap for 45 hours. Standard work-up and purification gave 4-[2-(4-methylsulfanyl-phenyl)-benzo[1,3]dioxol-2-yl]-piperidine as a white solid (286 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([C:26]#[C:27][C:28]([O:30]CC)=[O:29])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:18]=[C:17]([C:26]#[C:27][C:28]([OH:30])=[O:29])[CH:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C#Cc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C#Cc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 101.8 %

Procedure:
A mixture of ester 7.3 (68 mg, 0.157 mmol) and 1N LiOH (2 ml) in 6 ml MeOH/THF (1:2) was stirred at rt for 24 h, concentrated, and partitioned between Et2O and H2O. The organic phase was extracted with 0.1 N NaOH (2×), and the combined aqueous extracts were acidified with conc. HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with H2O, brine, and dried (Na2SO4) to afford 64 mg (100%) of acid 7.4. HRMS (ESI) calc'd for C25H25N2O3 401.1865, found 401.1855 (M+H+); 1H NMR (300 MHz, CDCl3) δ 7.48–7.37 (m, 5H), 7.26 (d, J=8.8, 2H), 7.08 (d, J=8.8, 2H), 6.51 (s, 1H), 5.13 (s, 2H), 4.15–4.06 (m, 1H), 2.05–1.97 (m, 2H), 1.90–1.87 (m, 4H), 1.28–1.23 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[Cl-].[NH4+]>O1CCCC1>[OH:18][CH2:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:8]=[N:9]2
Reactant: O=C(O)c1cccc2ncc(-c3ccccc3)cc12
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2ncc(-c3ccccc3)cc12
Reaction time: 1.5 h
Yield: 106.3 %

Procedure:
80 g (0.32 mol) of 3-phenyl-quinoline-5-carboxylic acid are suspended in 1.6 l of abs. tetrahydrfuran under argon and 400 ml of 1 molar lithium aluminum hydride solution in tetrahydrofuran are added dropwise. In this process, the temperature may rise to 35° C. The mixture is subsequently stirred for 90 minutes and 16 ml of water and then 48 ml of saturated ammonium chloride solution are added dropwise with cooling, the mixture is subsequently stirred for 30 minutes and filtered with suction, the solid is washed with tetrahydrofuran and the filtrate is concentrated. About 80 g of crude product are obtained. The melting point of the purified compound is 110°-112° C.
Reaction SMILES: C(O)C(O)C[O:4][P:5]([OH:13])([CH2:7][NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:6].C(CNC(CO)(CO)CO)CNC(CO)(CO)CO.[Cl-].[K+]>>[CH2:9]([NH:8][CH2:7][P:5]([OH:13])([OH:6])=[O:4])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)CNCP(=O)(O)OCC(O)CO
Agent: OCC(CO)(CO)NCCCNC(CO)(CO)CO
Agent: [Cl-]
Agent: [K+]
Product: O=C(O)CNCP(=O)(O)O
Reaction time: 1 h

Procedure:
The enzymatic reaction can be assayed using labelled (3-14C-) glyceryl glyphosate as a substrate and following the conversion to (3-14C-)glyphosate as a product using a high pressure liquid chromatography system with a radioactive detector. This assay is the most specific for the phosphonate monoester hydrolase enzymes useful for conditional cell lethality. An enzyme assay consists of 40,000 cpm of labelled (3-14C-) glyceryl glyphosate (obtained from NEN Biochemicals), the PEH sample in buffer and buffer to 100 μl final volume. The assay buffer is 10 mM Bis-Tris propane, pH 9.0, plus 100 mM KCl. The reaction is run for 1 hour at 30° C. and then stopped by the addition of 100 μl "quench" which is 100 mM sodium acetate, pH 5.5, in ethanol. The denatured protein is then spun down at 10,000 rpm in a microfuge and the supernatant transferred to an HPLC injection vial. A 100 μl aliquot is then injected onto an Synchropac AX100 anion exchange column 4.6×250 mm) pre-equilibrated in 65 mM potassium phosphate buffer, pH 5.5. The radioactive compounds are eluted isocratically for 15 min at 1 ml/min. The radioactivity of the peaks is measured and integrated by a post-column detector. Typically, the substrate elutes at 4.9 min and the product, glyphosate, at 9.7 min providing baseline separation. The radioactive glyceryl glyphosate has been found to be unstable where stored at -20° C. over a period of 3 months and must first be purified to remove glyphosate and any other contaminant. Alternatively, blank reactions can be included to determine the preexisting glyphosate contamination.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N=[N+]=[N-]
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@H]1N

Procedure:
Platinum oxide d (2.6 g) is added to a solution of 2.6 g of the azide in 150 ml of absolute ethanol, and the suspension is shaken with hydrogen gas for 1.5 hours at atmospheric pressure and room temperature. After the suspension is filtered three times on a celite column, the filtrate is evaporated to dryness. Recrystallization from CH2Cl2 -Et2O yields 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl amine.
Reaction SMILES: [NH2:1][C:2](=[O:38])[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]([CH3:7])C.N1CCC[C@@H]1C(N)=O>>[C:2]([C@H:3]1[CH2:4][CH2:5][CH2:7][N:8]1[C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:38])[NH2:1]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Agent: NC(=O)[C@H]1CCCN1
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)N2CCC[C@@H]2C(N)=O)C(C)(C)C)C1

Procedure:
Compound 75 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with (R)-pyrrolidine-2-carboxamide. LCMS (+ESI) m/z=521.5 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[S:24][C:25](Br)=[CH:26][CH:27]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31].C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.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].ClCCl>[CH2:1]([N:8]([CH2:22][C:23]1[S:24][C:25]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:30]([CH3:29])(=[O:32])=[O:31])[CH:38]=2)=[CH:26][CH:27]=1)[S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([F:21])([F:20])[F:19])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: O=S(=O)(c1ccccc1C(F)(F)F)N(Cc1ccccc1)Cc1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(Cc3ccccc3)S(=O)(=O)c3ccccc3C(F)(F)F)s2)c1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 85.7 %

Procedure:
Under argon to a stirred suspension of N-benzyl-N-(5-bromo-thiophen-2-ylmethyl)-2-trifluoromethyl-benzenesulfonamide (89 mg) and (3-methylsulfonylphenyl)-boronic acid (55 mg) in dioxane (0.5 mL), water (0.3 mL) and a 2 M Na2CO3 solution (0.27 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (7 mg). The mixture was stirred for 3.5 h at 80° C. Ethyl acetate was added and the mixture was washed with water. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 7:3) to give N-benzyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-2-trifluoromethyl-benzenesulfonamide (88 mg) as a light yellow oil. MS: 582.6 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27]O)[CH2:21][CH2:20]2)=[CH:17][C:16](=[O:29])[N:15]([CH3:30])[C:14]1=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:12][N:13]1[C:18]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][O:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[Cl:1])[CH2:21][CH2:20]2)=[CH:17][C:16](=[O:29])[N:15]([CH3:30])[C:14]1=[O:31]
Reactant: Cn1c(N2CCN(CCCO)CC2)cc(=O)n(C)c1=O
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCCOc3ccc([N+](=O)[O-])cc3Cl)CC2)cc(=O)n(C)c1=O
Yield: 47.7 %

Procedure:
In 70 ml of anhydrous tetrahydrofuran were suspended 2.4 g of 2-chloro-4-nitrophenol, 3.38 g of 1,3-dimethyl-6-[4-(3-hydroxypropyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound a) and 3.62 g of triphenylphosphine, and 2.4 g of diethyl azodicarboxylate was added to the resultant suspension. Afterward, the resultant mixture was treated in the same manner as in Reference Example 4 to obtain 2.5 g of light yellow crystals. The crystals were recrystallized from ethanol to obtain 2.07 g of crystalline 1,3-dimethyl-6-[4-(3-[2-chloro-4-nitrophenyloxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (Compound u).
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:30]([F:33])([F:32])[F:31])C1C=CC=CC=1>[Pd].CCO.C1COCC1.CC#N>[OH:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[C:30]([F:33])([F:32])[F:31]
Reactant: N#Cc1ccc(N(Cc2ccc(OCc3ccccc3)c(C(F)(F)F)c2)n2cnnc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC#N
Product: N#Cc1ccc(N(Cc2ccc(O)c(C(F)(F)F)c2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Palladium on charcoal (100 mg, 10% Pd) was added to a solution of 4-[(4-benzyloxy-3-trifluoromethyl-benzyl)-[1,2,4]triazol-4-yl-amino]benzonitrile (CAB03054, 1.75 g, 3.89 mmol) in EtOH/THF/MeCN (50 mL/50 mL/30 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 18 h at room temperature. The reaction mixture was filtered through celite and the clear colourless filtrate was concentrated under reduced pressure. The residue was suspended in 2-propanol (20 mL) and heated to reflux for 5 minutes. The white solid was filtered off after cooling to room temperature and dried under high vacuum. Yield: 1.31 g (94%). 1H-NMR (400. MHz, d6-DMSO) δ=4.98 (s, 2H), 6.78 (4, J=9.0 Hz, 2H), 6.91 (d, J=8.6 Hz, 1H), 7.31 (dd, J=8.6, 2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H), 7.76 (d, J=9.0 Hz, 2H), 8.74 (s, 2H), 10.66 (s, 1H, —OH). LRMS (FAB+): 360.2 (100, [M+H]+).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[S:17][C:16]([CH3:18])=[N:15][C:14]=3[C:19](O)=[O:20])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[CH3:30][NH2:31]>>[CH3:18][C:16]1[S:17][C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:28]=[N:27][CH:26]=[N:25][CH:24]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])=[C:14]([C:19](=[O:20])[NH:31][CH3:30])[N:15]=1
Reactant: CN
Reactant: Cc1nc(C(=O)O)c(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)s1
Agent: Cl
Product: CNC(=O)c1nc(C)sc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1

Procedure:
The product was obtained starting from 5-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-thiazole-4-carboxylic acid (28 mg, 0.07 mmol) and methylamine hydrochloride (6.2 mg, 0.09 mmol) according to the method described in example 64, step 6 as yellow solid (16 mg, 44%).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=2[C:19]#[N:20])=[N:10][CH:11]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([O:12][C:13]1[CH:14]=[C:15]([NH:21][C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=3)[CH:16]=[CH:17][C:18]=1[C:19]#[N:20])[N:10]=2
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc(N)cn3)c2)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(C#N)c(Oc3ccc4nc(N)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
Potassium thiocyanate (536 mg, 5.52 mmol) was suspended in acetic acid (10 mL), and the mixture was stirred at room temperature for 10 min. A solution of N-{3-[(5-aminopyridin-2-yl)oxy]-4-cyanophenyl}-3-(1-cyano-1-methylethyl)benzamide (550 mg, 1.38 mmol) in acetic acid (10 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (242 mg, 1.51 mmol) in acetic acid (7 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The yielded yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing fluid were combined, and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (100 mL), and the suspension was washed with 5% aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100). The obtained solution was concentrated under reduced pressure to give the title compound (0.51 g, 81%) as a pale-yellow amorphous substance.