Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1([CH3:17])[NH:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=2)=[N:6][C:5]1=[O:16])([CH3:3])[CH3:2].C([Li])CCC.C[O:24][C:25](=O)[C:26]([N:28]([CH3:30])[CH3:29])=[O:27].O>O1CCCC1>[CH3:29][N:28]([C:26](=[O:27])[C:25]([C:14]1[C:9]([C:7]2[NH:6][C:5](=[O:16])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:17])[N:8]=2)=[N:10][CH:11]=[C:12]([CH3:15])[CH:13]=1)=[O:24])[CH3:30]
Reactant: COC(=O)C(=O)N(C)C
Reactant: Cc1ccc(C2=NC(=O)C(C)(C(C)C)N2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)C(=O)N(C)C)c1
Temperature: -70 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a stirred solution of 2.5 g (0.011 mole) of 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2 -yl)-5-methyl pyridine in 100 ml of dry tetrahydrofuran cooled to -70° C. under the presence of nitrogen was added dropwise a 9.68 ml of 2.5 molar n-butyllithium, thereby temperature was maintained below -65° C. The solution was stirred at -70° C. for 3 hours and a solution 1.96 g of N,N-dimethyl oxamic acid methyl ester(0.015 mole) in 10 ml of anhydrous tetrahydrofuran was added dropwise while maintaining the temperature below -65° C. After stirring another hour at -70° C., the solution was poured into water and extracted with methylene chloride. The combined organic phases were dried over magnesium sulfate, and evaporated under reduced pressure. Trituration of the residue with diethyl ether affored a crude solid which was recrystallized from a mixture of diethyl ether and methylene chloride to yield 1.67 g of a white solid (m.p=180°-182° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[Cl-].[NH4+].C[N:33](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH2:33])=[O:28])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Yield: 51 %

Procedure:
Following the procedure for 243, 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid, ammonium chloride, HATU, diisopropylethylamine and DMF were reacted to give 104. Yield 51%. MS: 407.0. 1H NMR (400 MHz, DMSO) δ 8.21 (s, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.74 (d, J=7.0, 1H), 7.69-7.54 (m, 4H), 7.47 (s, 1H), 7.44-7.36 (m, 2H), 4.48 (d, J=7.6, 4H)
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9](OS(C(F)(F)F)(=O)=O)[CH:10]=1.[CH3:36][Zn]C>O1CCOCC1.C1(C)C=CC=CC=1.[Pd].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:1][C:2]1[CH:26]=[C:25]([S:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:19][C:20]([OH:22])=[O:21])[CH:8]=[C:9]([CH3:36])[CH:10]=1
Reactant: C[Zn]C
Reactant: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)cc(OS(=O)(=O)C(F)(F)F)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: Cc1cc(CC(=O)O)cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared by treating the product from step (ii) (0.25 g) in dry dioxane (10 ml) with bisdiphenylphosphinoferrocene palladium (0.02 g) and 2.0M dimethylzinc in toluene (0.40 ml). The mixture was heated to reflux for 3 h, partitioned between water and ethyl acetate, the organics separated, dried (MgSO4) and evaporated under reduced pressure to an oil. The oil was dissolved in methanol (10 ml), 2M NaOH (10 ml) added and stirred at RT overnight. The mixture was diluted with water, extracted with ether (discarded). The aqueous layer was acidified with 2M HCl, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to an oil, which was purified by RPHPLC to give a white solid (0.085 g).
Reaction SMILES: [C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([O-:17])=[O:16])#[N:2].C([N+](CCCC)(CCCC)CCCC)CCC.C1CCCCC1>C(OCC)(=O)C>[C:1]([N:3]1[C:7](=[O:8])[C:6]([CH:10]([CH3:12])[CH3:11])([CH3:9])[N:5]=[C:4]1[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])#[N:2]
Reactant: CC(C)C1(C)N=C(c2ncccc2C(=O)[O-])N(C#N)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC(C)C1(C)N=C(c2ncccc2C(=O)O)N(C#N)C1=O
Yield: 42 %

Procedure:
Tetrabutylammonium 2-(1-cyano-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinate (0.36 g, 0.00068 mol) is placed into a mixture of cyclohexane and ethyl acetate for 3 months. The mixture is filtered to yield the title compound as a tan solid (0 09 g 42%) mp 150°-153° C. identified by IR and NMR spectral analyses.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[N:18][C:19]#[N:20])OC2C=CC=CC=2)[CH:6]=[CH:7][CH:8]=1.[CH:23]1([NH2:28])[CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCl>[C:19]([NH:18][C:10]([NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[N:28][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)#[N:20]
Reactant: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Reactant: NC1CCCC1
Solvent: ClCCl
Product: N#CNC(=NC1CCCC1)Nc1cccc(C(F)(F)F)c1
Yield: 68 %

Procedure:
N-(3-Trifluoromethylphenyl)-N'-cyano-O-phenylisourea (1 mmol, 290 mg) was stirred for 19 h at 80° C. in cyclopentylamine (1 ml). After concentration of the cold reaction mixture, the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (heptane:ethyl acetate 3:1) to give the title compound (205 mg, 68%) as a syrup. Crystallisation from heptane:ethyl acetate 2:1 gave 147 mg (49%). Mp 111.5-113° C; 1H-NMR (CDCl3): δ 1.42 (m, 2H), 1.65 (m, 4H), 2.05 (m, 2H), 4.12 (sextet, 1H), 4.85 (br, 1H), 7.35 (br s,1H), 7.5 ppm (m, 4H); MA calc for C14H15F3N4 : C, 56.75%; H, 5.10%; N, 18.91%. Found: C, 56.48%; H, 5.08%; N, 18.65%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CC(CC(C)C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:11][CH:10]=2)=[O:16])=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)C(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1

Procedure:
0.75 mole (175 g) of 4'-chloro-4-hydroxy-benzophenone, 1.5 l of methylisobutyl ketone, 0.975 mole (134 g) of K2CO3 and 0.8 mole (145 g) of ethyl 2-bromopropionate are placed in a 2-liter flask. The mixture is heated at reflux for 8 hours with vigorous agitation whereupon the reaction mixture is cooled and filtered on a Buchner funnel. The solvent is then evaporated under vacuum and the residue distilled; the desired ester is recovered at 198° to 201° C under 0.1 mm of mercury. Yield 190 g (76%).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[CH:14]1([N:20]=[C:21]=[O:22])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:2]([N:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8]/[C:7]/1=[CH:13]\[C:21]([NH:20][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:22])[CH2:3][CH2:4][CH3:5]
Reactant: O=C=NC1CCCCC1
Reactant: CCCC[n+]1c(C)sc(C)c1C
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of Example 1A (123 mg, 0.4 mmol) and cyclohexyl isocyanate (63 mg, 0.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of DBU (0.076 mL, 0.5 mmol) in CH2Cl2 (5 mL). The mixture was allowed to warm to room temperature and stirred for 14 hours. The mixture was washed sequentially with water, brine and dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (CH2Cl2-MeOH 9:1) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (t, J=7 Hz, 3H), 1.10 (m, 3H), 1.29 (m, 4H), 1.51 (m, 3H), 1.70 (m, 4H), 1.95 (s, 3H), 2.02 (s, 3H), 3.33 (m, 3H), 5.02 (s, 1H), 6.74 (br d, J=7 Hz, 1H); MS (ESI) m/z 309 (M+H)+. Anal calcd for C17H28N2OS.0.25H2O: C, 65.24; H, 9.18; N, 8.95. Found: C, 65.49; H, 9.30; N, 8.93.
Reaction SMILES: [C:1]([O:4][C:5]1[C:13]2[C:8](=[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1)(=[O:3])[CH3:2].C(Cl)(=O)[C:25]1[CH:30]=[CH:29]C=[CH:27][CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:13]2[C:8](=[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]=1)(=[O:3])[C:2]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC1=CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: O=C(OC1=CCc2c(Oc3ccc([N+](=O)[O-])cn3)cccc21)c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To 500 mg of 3-acetyloxy-7-[(5-nitro-2-pyridinyl)oxy]-1H-indene, 5 ml of benzoyl chloride and 15 mg of p-toluenesulfonic acid were added and the mixture was stirred at 100° C. After 1.5 hours, ethyl acetate was added to the reaction solution and the solution was washed in turn with a saturated sodium hydrogencarbonate solution and a saturated sodium chloride solution. The solution extracted with ethyl acetate was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (10:1)) to obtain 130 mg of the titled compound as a white powder.
Reaction SMILES: [F:1]C1C(F)=C(F)C(F)=C(F)C=1F.C(=O)=O.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]2[N:24]=[C:25]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:26]([C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[C:19]2[CH:18]=1>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.CC(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([F:1])[N:20]2[N:24]=[C:25]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[C:26]([C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:28])=[C:19]2[CH:18]=1
Reactant: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cc(Cl)cc12
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [C-]#N
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C(=O)OC(C)(C)C)C(=O)c1c(-c2ccc(F)cc2)nn2c(F)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution containing tetrabutylammoniumcyanide and THF (0.912 mL, 1.0 M) was added a solution containing hexafluorobenzene and THF (0.760 mL, 0.2 M) at −35° C. (caution, exothermic). The solution was removed from cooling and maintained at ambient temperature for 150 min. The solution thus obtained was cooled to 0° C. (ice bath) and added dropwise with stirring to a pre-cooled solution (−50° C., dry ice, acetone) containing tert-butyl 5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate and THF (0.608 mL, 0.38 M). The solution thus obtained was removed from cooling and allowed to proceed for 18 h. The solution was poured into water (25 mL). The aqueous portion was then extracted with ethyl acetate (2×25 mL). The organic portions were combined, then washed with water (3×20 mL), then washed with brine (25 mL), then dried over MgSO4, filtered and concentrated. The residue thus obtained was purified on silica gel (0-20% ethyl acetate/hexanes, 25 min gradient) to afford tert-butyl 5-chloro-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.65-7.76 (m, 3H), 7.11-7.20 (m, 2H), 6.64 (dd, J=4.77, 2.01 Hz, 1H), 3.27 (s, 3H), 1.12 (s, 9H). LCMS retention time: 2.743 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 422 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.6 %

Procedure:
To a stirred solution of 3-phenyl-1H-indole-2-carboxylic acid ethyl ester (3.99 g, 15.0 mmol) in DMF (25 mL) cooled to 0° C. and under a nitrogen atmosphere was added NaH (60% in mineral oil, 720 mg, 18.0 mmol). After stirring for 10 min at RT, the reaction mixture was cooled to 0° C. and 4-methylbenzenesulfonyl chloride (3.44 g, 18.0 mmol) in DMF (15 mL) was added. Stirring was continued for 16 h at RT then the mixture was poured into 1.0M HCl and extracted with EtOAc (×2). The combined organic layers were washed with water, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 30-100% DCM in pentane) affording 3-Phenyl-1-(toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester as a colourless oil (3.25 g, 52%). 1H NMR (CDCl3, 400 MHz): δ 8.08 (1H, d, J=8.43 Hz), 7.92 (2H, d, J=8.37 Hz), 7.53-7.36 (7H, m), 7.28-7.21 (3H, m), 4.35 (2H, q, J=7.15 Hz), 2.36 (3H, s), 1.25 (3H, t, J=7.14 Hz).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:50])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=2)[CH:41]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=5)[C:39]([F:50])=[CH:38][CH:37]=4)=[O:27])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (446 mg, 1 mmol) in DMF (70 mL) was added [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (230 mg, 1 mmol), PyBOP (570 mg, 1.1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) and the mixture was stirred at ambient temperature for 16 h. Additional PyBOP (518 mg, 1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) were added and the mixture stirred for an additional 2 h. The mixture was then concentrated to dryness and the residue was treated with water (400 mL) and extracted with dichloromethane (2×200 mL). The combined organics were dried (hydrophobic frit) and concentrated in vacuo and the resulting yellow oil was subjected to purification by flash chromatography (100 g silica cartridge, gradient elution from 0-100% ethyl acetate/cyclohexane) to afford 650 mg of the title compound. LC-MS m/z 665 (M+H)+, 0.98 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH3:18])=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:29]([Li])([CH2:31]C)[CH3:30].C(Br)C=C>O1CCCC1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C:17]([CH2:18][CH2:31][CH:29]=[CH2:30])=[C:16]2[C:11]([CH2:12][CH2:13][C@H:14]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:15]2)=[CH:10][CH:9]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: [Li]C(C)CC
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCCc1c(NC(=O)OC(C)(C)C)ccc2c1O[C@@H](C(C)(C)O[SiH2]C(C)(C)C)CC2
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a solution of (2R)-[2-(tert-butyl-dimethyl-silanyloxymethyl)-8-methyl-chroman-7-yl]-carbamic acid tert-butyl ester (0.41 g, 1 mmole) in anhydrous tetrahydrofuran (20 mL) containing 10 mg of 1,10-phenanthroline at −40° C. was slowly added 2.4 equivalents of 1.3 M s-butyl lithium. After 1 equivalent of s-butyl lithium had been added, the deep red color of the indicator became apparent. The reaction was allowed to stand for 1.5 hours, after which allyl bromide (0.24 g, 2.0 mmole) was added. The reaction was allowed to stand for an additional 4 hours and then was quenched with water (4 mL). The reaction mixture was next diluted with ether (250 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was separated and the solvent removed under vacuum. Column chromatography on silica gel (5% methylene chloride/hexane) afforded 0.37 g (75%) of the title compound as an oil, [α]25D=−32.42° (3.7, THF).
Reaction SMILES: CN1C(=O)C(C)(N2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([F:22])[C:13]([F:21])=[C:14]([F:20])[C:15]=3[F:19])[C:10]2=[O:23])C(=O)NC1=O.Cl.[NH2:28][C:29]1([CH2:41][CH3:42])[C:34](=[O:35])[N:33]([CH2:36][CH2:37][CH3:38])[C:32](=[O:39])[NH:31][C:30]1=[O:40]>>[CH2:41]([C:29]1([N:28]2[C:10](=[O:23])[C:11]3[C:16](=[C:15]([F:19])[C:14]([F:20])=[C:13]([F:21])[C:12]=3[F:22])[C:17]2=[O:18])[C:34](=[O:35])[N:33]([CH2:36][CH2:37][CH3:38])[C:32](=[O:39])[NH:31][C:30]1=[O:40])[CH3:42]
Reactant: CN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Reactant: CCCN1C(=O)NC(=O)C(N)(CC)C1=O
Agent: Cl
Product: CCCN1C(=O)NC(=O)C(CC)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O

Procedure:
Compound 19e was synthesized in the same manner as described for 19a from 5-amino-5-ethyl-1-propylbarbituric acid hydrochloride (0.38 g, 1.50 mmol). The crude product was recrystallized from EtOH (70%) to give 5-ethyl-1-propyl-5-(tetrafluorophthalimido)-barbituric acid (19e) as white crystals.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23](O)=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:27][O:28][C@@H:29]([C@@H:38]([N:43]([CH3:51])[C:44](=[O:50])[C@H:45]([CH:47]([CH3:49])[CH3:48])[NH2:46])[C@@H:39]([CH3:42])[CH2:40][CH3:41])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>CC1CCCO1>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]([CH3:26])[C@H:19]([C:23]([NH:46][C@H:45]([C:44]([N:43]([C@@H:38]([C@@H:39]([CH3:42])[CH2:40][CH3:41])[C@H:29]([O:28][CH3:27])[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])[CH3:51])=[O:50])[CH:47]([CH3:49])[CH3:48])=[O:24])[CH:20]([CH3:21])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC1CCCO1
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 0.17 h
Yield: 108.4 %

Procedure:
To a mixture of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N-methyl-L-valine (19.54 g, 55.29 mmol, 1.3 eq.) and #6 (15.25 g, 42.54 mmol, 1 eq.) in 2-methyltetrahydrofuran (152 mL, 0.28 M) was added 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.71 g, 55.3 mmol, 1.3 eq.). After 10 minutes, N-methylmorpholine (6.6 mL, 60 mmol, 1.4 eq.) was slowly added, while keeping the internal temp below 25° C. The reaction was stirred for 4 hours and was then quenched by the addition of water (50 mL). After stirring for 15 minutes, the aqueous layer was separated and back-extracted with 2-methyltetrahydrofuran (50 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (100 mL), then were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting yellow foam was purified by silica gel chromatography (Gradient: 5% to 35% ethyl acetate in heptane) to give #7 (32 g, 97%). 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.89 (d, J=7.4 Hz, 2H), 7.62 (d, J=7.4 Hz, 2H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.29-7.34 (m, 2H), 4.52-4.69 (br m, 1H), 3.70-3.82 (br m, 1H), 3.22 and 3.25 (2 br s, total 3H), 2.94 and 2.96 (2 br s, total 3H), 2.78 and 2.81 (2 br s, total 3H), 2.11-2.23 (m, 1H), 1.90-2.10 (m, 2H), 1.68-1.83 (br m, 1H), 1.40 (s, 9H), 1.21-1.33 (br m, 1H).
Reaction SMILES: [CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:20]([OH:22])=[O:21].[CH3:23]O>O>[CH2:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([O:22][CH3:23])=[O:21]
Reactant: CO
Reactant: O=CO
Agent: CCCCCCN(CCCCCC)CCCCCC
Solvent: O
Product: COC=O

Procedure:
Example 1 was carried out in laboratory plant 1. 1760 g/h of methyl formate via stream (1a) and 849 g/h of water via stream (1c) were metered by means of metering pumps into the stirred vessel A1. Stream (1c) was taken from the mixing vessel X and was composed of fresh water via stream (1b) and recycled water from the distillation apparatus B2 via stream (3c). Stream (1b) was selected so that the sum of stream (1b) and stream (3c) gave the desired stream (1c). The stirred vessel A1 was operated at 110° C. and 1.3 MPa abs. The output was introduced into tube reactor A2 which was likewise operated at 110° C. and 1.3 MPa abs. The output from tube reactor A2 was introduced into tube reactor A3. 1964 g/h of tri-n-hexylamine were fed via stream (8a) into this tube reactor A3. The output from tube reactor A3 was introduced into tube reactor A4. A further 1661 g/h of tri-n-hexylamine were fed via stream (8b) into this tube reactor A4. The streams (8a) and (8b) were taken from the vessel Y which served to distribute the tri-n-hexylamine recirculated via stream (8) to the two tube reactors A3 and A4. Tube reactor A3 was operated at 115° C. and 1.3 MPa abs, and tube reactor A4 was operated at 110° C. and 1.3 MPa abs. A product mixture comprising 58.4% by weight of tri-n-hexylamine, 16.4% by weight of formic acid, 12.3% by weight of methanol, 7.8% by weight of water and 6.9% by weight of methyl formate was obtained as stream (2).