Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C#N)cc1
Yield: 94.3 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.502 g, 1.83 mmol), α-bromo-p-tolunitrile (0.538 g, 2.75 mmol), KI (65 mg, 0.40 mmol), and DIPEA (0.72 mL, 4.13 mmol) in DMF (9 mL) was heated at 60° C. for 16 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.66 g (94%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a white solid. 1H NMR (CDCl3) δ 1.60-1.73 (m, 3H), 2.02-2.12 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.56 (s, 2H), 4.14 (d, 2H, J=10.5 Hz), 6.64 (d, 2H, J=8.1 Hz), 6.95 (dd, 2H, J=7.5, 4.8 Hz), 7.10 (d, 2H, J=7.8 Hz), 7.22 (d, 2H, J=7.2 Hz), 8.37 (d, 2H, J=3.9 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH:22]=O)[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:26][C@H:27]([CH3:30])[CH2:28][OH:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][NH:26][C@H:27]([CH3:30])[CH2:28][OH:29])[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=CCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: C[C@@H](N)CO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H](CO)NCCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 73 %

Procedure:
The titled compound was prepared from N-(1-adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide (Example 3(ii)) (0.10 g), (R)-2-aminopropanol (0.046 g) and sodium cyanoborohydride (0.020 g) in methanol (3 ml) and acetic acid (0.1 ml) by the method of Example 3(iii). The product was purified by chromatography on silica gel eluting with 0.7M anhydrous ammonia in methanol:ethyl acetate (1:5) to afford the titled compound as an oil (0.085 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][CH2:35]N=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(O)C>CN(C=O)C>[CH2:34]([O:14][C:13](=[O:15])[C@@H:12]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46 %

Procedure:
In DMF (50.0 ml), 5-t-butoxycarbonylamino-(2S)-(9H-fluoren-9-ylmethoxycarbonylamino)-pentanoic acid (2.50 g) was dissolved. The solution was added with WSCI hydrochloride (1.21 g) and HOBt (0.84 g) and the whole was stirred at room temperature for 1.5 hours. The solution was added with ethanol (1.0 ml) and the whole was stirred at room temperature for additional 17 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.22 g) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH:6]=[CH:7][C:8](=O)[CH2:9]C(OC)=O)#[N:2].[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][O:24][C:25](=[O:30])/[CH:26]=[C:27](\[NH2:29])/[CH3:28]>CCO>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][O:24][C:25]([C:26]1[CH:6]([C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([C:1]#[N:2])[CH:4]=2)[C:7]([C:25]([O:24][CH3:23])=[O:30])=[C:8]([CH3:9])[NH:29][C:27]=1[CH3:28])=[O:30]
Reactant: COC(=O)CC(=O)C=Cc1cccc(C#N)c1
Reactant: C/C(N)=C/C(=O)OCC1CCCO1
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(C#N)c1
Temperature: -10 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A solution of 30 g (0.13 mol) of methyl 3-cyanobenzylideneacetoacetate and 24.24 g (0.13 mol) of (tetrahydrofuran-2-ylmethyl)-3-aminocrotonate in 130 ml of abs. ethanol was refluxed with stirring, in the absence of light, along 8 hours. The reaction mixture was then cooled to −10° C., and the product was obtained as a yellow solid (mp 127-9° C., EtOH) with a yield of 79%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:7]1[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH:24]=[O:25])[CH:27]=2)=[CH:3][C:4]([CH2:9][N:10]([CH3:23])[C:11]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:12])=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(Br)c2)c1
Reactant: O=Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cccc(C(=O)N(C)Cc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Temperature: 130 °C
Yield: 86.3 %

Procedure:
To a solution of methyl 3-{[[(3-bromo-4-fluorophenyl)methyl]-(methyl)amino]carbonyl}benzoate (0.20 g, 0.526 mmol) in p-dioxane/H2O (4.5/1.5 mL) was added (4-formylphenyl)boronic acid (0.118 g, 0.789 mmol), Pd(PPh3)4 (0.030 g, 0.026 mmol), and K2CO3 (0.29 mL, 2.1 mmol). The mixture was heated in a microwave at 130° C. for 15 min. It was then filtered, concentrated and the concentrate purified by CombiFlash chromatograph to afford the title compound 0.184 g (86%). LC-MS m/z 406 (M+H)+.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16]>O1CCOCC1.[OH-].[Na+]>[CH2:1]([S:3]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)NCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
A solution of ethanesulfonyl chloride (1.5 ml, 15.7 mmol) in dioxane (5 ml) was added to a solution of 8-aminooctanoic acid (1 g, 6.28 mmol) in 1N NaOH (22 ml) and dioxane (5 ml), while stirring at 0° C.-5° C. The mixture was allowed to warm to room temperature and stirred for 3.5 minutes. During this period, at 1 hour intervals, the pH was adjusted to 7-8 by addition of 25% NaOH solution. The reaction mixture was washed with diethyl ether (30 ml). The pH was adjusted to 1-2 by addition of 1N HCl and the mixture was extracted with ethyl acetate (70 ml). The organic layer was dried over sodium sulfate and concentrated. The residue was triturated with a mixture of diethyl ether. The solid was collected by filtration and dried under vacuum affording 600 mg of the title compound (38% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.O>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([CH2:14][Br:24])=[C:12]([CH:15]([CH3:17])[CH3:16])[N:11]=[C:10]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CBr
Yield: 100.9 %

Procedure:
N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (112.5 mg, 0.33 mmol, 1 equiv.) and N-bromosuccinimide (NBS) (126 mg, 0.72 mmol, 2.1 equiv.) were dissolved in 2 mL of acetonitrile. The mixture was irradiated with light of a wavelength A=310 nm for 4 hours at ambient temperature (about 20° C.). Then, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with 10 mL of brine, and the obtained solution was dried with Na2SO4. Solvent was removed under the reduced pressure to give 138.6 mg of crude N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II), which contained 93% of N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II) as determined by 1H-NMR integral. This product can be further purified by crystallization from MTBE/hexane mixture to afford pure material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:15])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].O1CCCC1.[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH2:28]>C(N(CC)CC)C>[CH3:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[NH:28][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([F:1])[C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:9]([F:15])[CH:8]=1
Reactant: CC1CCCCC1N
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCOc1c(F)cc(C(=O)NC2CCCCC2C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 346 mg of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride and 1 ml of tetrahydrofuran was added dropwise under ice cooling to a mixture of 5 ml of tetrahydrofuran, 170 mg of 2-methylcyclohexylamine and 182 mg of triethylamine. The mixture obtained was stirred at room temperature for 0.5 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 295 mg of N-(2-methylcyclohexyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 42 of the present invention) represented by the formula:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:10])[CH2:8][CH3:9]>>[C:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:10])[CH2:8][CH3:9]
Reactant: C1CCNCC1
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCCCC1

Procedure:
This compound was prepared by a method analogous to that of description 9 using piperidine in place of heptamethyleneimine and propionyl chloride in place of acetyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([C:27]#[N:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[OH:38]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]1[C:21]1[CH:26]=[C:25]([C:27](=[O:38])[NH2:28])[CH:24]=[CH:23][C:22]=1[O:29][CH2:30][C:31]([OH:33])=[O:32])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CCOC(=O)COc1ccc(C#N)cc1C1c2ccccc2CCN1C(=O)OCc1ccccc1
Solvent: O
Product: NC(=O)c1ccc(OCC(=O)O)c(C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of (±)-1-(5-cyano-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (141 mg, 0.30 mmol, 1.0 eq.) in EtOH (0.5 mL) and water (0.12 mL), hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphinito-kP)]platinum(II) (26 mg, 0.06 mmol, 0.2 eq.) was added in one portion at r.t. The reaction mixture was stirred at 70° C. for 1 hour, then allow to cool to r.t. The product solution was then filtered through a short column containing a layer of Na2SO4 on top of a layer of SiO2 (each 1 cm deep), eluting with AcOEt (200 mL). The filtrate was concentrated in vacuo. To a solution of the residue in DMF (2 mL), 1M aq. NaOH (0.5 ml) was added. The resulting solution was stirred at r.t. for 6 hours. The mixture was neutralized with formic acid (0.5 mL), filtered, and purified by prep. HPLC (column: Waters X-Bridge, 19×50 mm, 5 um, UV/MS, acidic conditions) to give the desired acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10](Cl)[N:9]=[C:8]2Cl.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[N:9]=[C:8]([N:11]([C:12]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:10])[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=2)[N:11]=1
Reactant: COc1cccc2c(Cl)nc(Cl)nc12
Reactant: CNc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc2c(N(C)c3ccccc3)nc(N(C)c3ccccc3)nc12
Yield: 15 %

Procedure:
8-Methoxy-2,4-dichloroquinazoline (1.5 g, 0.007 mol) was heated under reflux in a solution of N-methyl aniline (1.43 m), 0.014 mol) in tetrahydrofuran (50 ml) for 16 hours precipitating a solid, which was collected and crystallised from ethanol/water to give 2,4-bis-(N-methylphenylamino)-8-methoxyquinazoline (0.37 g, 15%), m.p. 169°-170°.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=2)=[CH:26][N:25]=1>CN(C=O)C>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:24]3[N:25]=[CH:26][C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=4)=[CH:28][N:29]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1OC
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)OCO4)nc2)cc1OC

Procedure:
Following the same procedure as outlined in Example 12, 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (3.73 g, 12.8 mmol) (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) and 2-chloro-5-(3,4-dimethoxylphenyl)pyrimidine (1.60 g, 6.4 mmol) in DMF (50 mL, anhydrous) were reacted to yield the product as a white solid.
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=2)[CH:4]=1.[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH:42][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([CH:2]([F:1])[F:26])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[C:17]([CH3:25])[CH:16]=5)=[N:6][C:7]=34)=[O:14])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)N5CCOCC5)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.5) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 595.2 [(M+H)+]; mp 261° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([O:26][CH3:27])=[C:21]([CH:25]=1)[C:22](Cl)=[O:23]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:22](=[O:23])[C:21]2[CH:25]=[C:17]([Cl:16])[CH:18]=[CH:19][C:20]=2[O:26][CH3:27])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)c1ccc(N)cc1OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(Cl)ccc2OC)cc1OCC
Reaction time: 3 h

Procedure:
10.4 g of 2-ethoxy-4-amino-benzoic acid ethyl ester were suspended in a mixture of 6.8 ml of triethylamine and 200 ml of toluene and 10.3 g of 5-chloro-2-methoxy-benzoyl chloride dissolved in a small amount of toluene were added dropwise. The whole was stirred for 3 hours under reflux and, after cooling, it was washed with water, dilute hydrochloric acid and a sodium bicarbonate solution and dried over sodium sulfate. Upon concentration of the solution under reduced pressure, the 2-ethoxy-4-(5-chloro-2-methoxy-benzamido)-benzoic acid ethyl ester was obtained in the form of a solid product having a crude melting point of 108°-111° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1C=CC=CC=1>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]=[N:16][C:17]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:18]=2[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=2)=[O:20])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C=Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution containing 1-Boc-piperidine-4-carboxaldehyde (3.0 g, ca. 14 mmol), 2-amino-N-(5-chloropyridin-2-yl)-5-fluorobenzamide (3.7 g, 14 mmol), and pyridinium p-toluene-sulfonate (0.3 g, 1.4 mmol) in benzene (250 mL) was heated at reflux for 24 h with azeotropic removal of water. The solution was allowed to cool to room temperature; then the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (300 mL) and water (150 mL). The organic phase was separated and washed again with water (150 mL) and then brine (150 mL); then dried with MgSO4, filtered and concentrated in vacuo to give 6.0 g (93%) of the title compound as an orange foam which was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[CH:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:4]([NH:24][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:6])=[CH:7][CH:8]=[C:9]([Cl:11])[N:10]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)c1ccc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,6-dichloronicotinic acid (5.005 g, 26.18 mmol) in DCM (60 ML) was added a few drops of DMF followed by the addition dropwise of oxalyl chloride (2.27 mL, 26.18 mmol). The reaction was stirred at room temperature for two hours until gas bubbling had stopped. The solvent was evaporated under reduced pressure to give an oil. DCM (60 mL) was added and the reaction mixture was cooled in an ice bath. Cyclohexylamine (5.98 mL, 52.36 mmol) was added slowly keeping the temperature below 15° C. The reaction was stirred at room temperature overnight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH:17]1[CH:21]=[C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[N:19]=[CH:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:26][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:19]=[CH:18][NH:17][CH:21]=2)=[CH:28][CH:27]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(-c2c[nH]cn2)cc1
Temperature: 120 °C

Procedure:
A mixture of 2.00 g (7.09 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 1.24 g (7.80 mmol) of 4-(1H-Imidazol-4-yl)aniline in 22 mL of N,N-dimethylformamide (DMF) is heated at 120° C. for 1.25 h. The chilled reaction mixture is filtered and the insoluble material is washed with N,N-dimethylformamide (DMF) and Et2O. In order to remove residual N,N-dimethylformamide (DMF), the solid is boiled with MeOH (2×), washed with Et2O and dried in vacuo. The yield is 2.10 g (72%) of yellow-brown crystals: mp >300° C. (dec); 1H NMR (DMSO-d6) δ 12.6 (d, 1H, J=12.7 Hz), 12.2 (s, 1H), 11.4 (s, 1H), 8.98 (d, 1H, J=12.7 Hz), 8.49 (s, 1H), 7.86 (m, 3H), 7.67 (m, 4H), 7.41 (d, 1H, J=8.34 Hz); HRMS (ESI) m/e calcd for C19H13BrN4O2 409.02947. found 409.02902 (M+H)+1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19].CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.4 %

Procedure:
A flask charged with 1H-imidazole-2-carboxylic acid ethyl ester (1.03 g, 7.36 mmol), K2CO3 (2.00 g, 14.5 mmol), SEM-Cl (1.56 mL, 8.89 mmol), and 20 mL of acetone was stirred for 10 h at RT. The reaction was diluted with EtOAc (100 mL), washed with NaHCO3 (2×100 mL), brine (100 mL), and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 50% EtOAc/hexanes to give 1.50 g (76%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H22N3O3Si, 271.1 (M+H). found 271.1.
Reaction SMILES: [P:1]([O:5][CH2:6][CH:7]([OH:10])[CH:8]=[O:9])([OH:4])([OH:3])=[O:2].C(O)[CH:12]([OH:19])[CH2:13][O:14]P(O)(O)=O.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[P:1]([O:5][CH2:6][C@@H:7]([OH:10])[C@@H:8]([OH:9])[C@@H:12]([OH:19])[CH:13]=[O:14])([OH:4])([OH:3])=[O:2]
Reactant: O=CC(O)COP(=O)(O)O
Reactant: O=P(O)(O)OCC(O)CO
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: O=C[C@H](O)[C@H](O)[C@H](O)COP(=O)(O)O
Temperature: 30 °C

Procedure:
Crude cell extracts were prepared in 100 mM Tris/HCl at pH 7.8. Determination of TKT activity required application of several coupling enzymes. RPI and RPE served as coupling enzymes to provide the substrates ribulose 5-phosphate and xylulose 5-phosphate from ribose 5-phosphate (R5P) supplied in the assay. Online monitoring at 340 nm was enabled by further conversion of glyceraldehyde 3-phosphate as product of the TKT reaction by triosephosphate isomerase and glycerophosphate dehydrogenase (TPI/GDH). In contrast to the above mentioned procedure, two distinct mastermixes were prepared. Mix A contained buffer, TPI, RPI, RPE and NADH in a total volume of 650 μl, mix B contained buffer, TPP, MgCl2 and cell extract in a total volume of 300 μl. Both were pre-warmed for 10 min at 30° C. Ribose 5-phosphate was provided in the cuvette and the reaction was started by subsequent addition of mix B and mix A. The final reaction mix contained 50 mM Tris/HCl (pH 7.8), 0.5 mM NADH, 1 U RPI, 0.5 U RPE, 1 U TPI/GDH, 10 mM MgCl2, 0.2 mM TPP, 20 mM R5P and 50 μl of crude cell extract.