Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:26])=[C:19]([CH:27]([CH3:29])[CH3:28])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:35][O:34][C:32](=[O:33])[CH2:31][O:26][C:20]1[C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:18][C:19]=1[CH:27]([CH3:29])[CH3:28]
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(C(C)C)c(O)c(C(C)C)c3)c2c1C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(C(C)C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C(C)C
Yield: 87.5 %

Procedure:
A solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenol (0.42 g, 0.89 mmol), methyl bromoacetate (0.36 mL, 3.8 mmol), and potassium carbonate (0.42 g, 3.0 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) at room temperature under nitrogen was stirred for 2 days. The reaction mixture was diluted with water and extracted with diethyl ether. Concentration under reduced pressure and chromatography with petroleum ether:ethyl acetate (95:5) gave the title compound as a white solid (0.42 g, 87%): NMR (DMSO-d6): δ 8.20 (d, 1H), 7.66-7.61 (m, 1H), 7.48 (d, 2H), 7.11 (s, 2H), 4.56 (s, 2H), 3.77 (s, 3H), 3.42-3.27 (m, 2H), 2.42 (s, 3H), 1.51 (s, 3H), 1.18 and 1.16 (two doublets, 12H).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]2[N:27]=[C:26]([CH3:28])[C:25]([C:29](=O)[CH2:30][CH2:31][CH3:32])=[C:21]2[O:22][C:23]=1[CH3:24]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[N:20]2[N:27]=[C:26]([CH3:28])[C:25]([C:29](=[CH2:1])[CH2:30][CH2:31][CH3:32])=[C:21]2[O:22][C:23]=1[CH3:24]
Reactant: CCCC(=O)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(CCC)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (0.814 g, 2.278 mmol) in THF (8 ml) is added 1.0M NaHMDS (in THF) (2.278 ml, 2.278 mmol) generating a yellow reaction mixture. After stirring at RT for 10 minutes, 1-[3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-yl]-butan-1-one (0.400 g, 1.139 mmol) is added and the reaction mixture is stirred at RT for 16 hours: a tan solution turning brown O/N. The reaction is quenched with ammonium chloride (sat. aq. 2 ml). The reaction mixture is partitioned between EtOAc (50 ml) and H2O (50 ml) and extracted with EtOAc (3×20 ml). The combined organic extracts are washed with brine (1×50 ml), dried Na2SO4, filtered and concentrated in vacuo. The resulting residue is purified via Flashmaster SiO2 150 ml/50 g column eluting with 12:1 Iso-hexane/EtOAc to yield the title compound as a white crystalline solid; MS: 349.08 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.77 (1H, d), 7.59 (1H, d), 7.51 (1H, dd), 4.94 (1H, d), 4.85 (1H, d), 2.30 (3H, t), 2.18 (3H, s), 2.14 (3H, s), 1.35 (2H, m), 0.79 (3H, t).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:17])[NH:9][NH:10][C:11]2=[O:16])=[O:4].[OH-].[NH4+:19]>>[NH2:19][CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:17])[NH:9][NH:10][C:11]2=[O:16])=[O:4]
Reactant: O=C(CCl)Nc1cccc2c(=O)[nH][nH]c(=O)c12
Reactant: [NH4+]
Agent: [OH-]
Product: NCC(=O)Nc1cccc2c(=O)[nH][nH]c(=O)c12

Procedure:
forming a second reaction mixture comprising the 2-Chloro-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide and ammonium hydroxide, to yield 2-Amino-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide; and
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[O:11]=[C:12]1[NH:16][CH2:15][C@H:14]2[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][C@@H:13]12>>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:16]2[C:12](=[O:11])[C@@H:13]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@@H:14]3[CH2:15]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CNC(=O)[C@@H]2C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc([N+](=O)[O-])nc3)C(=O)[C@@H]2C1
Yield: 81.8 %

Procedure:
Following general N—C coupling procedure 1, 5-bromo-2-nitropyridine (4.71 g, 23.2 mmol, 1.05 eq) was combined with cis-tert-butyl 4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5 g, 22.1 mmol, 1.0 eq), which after silica gel purification gave cis-tert-butyl 5-(6-nitropyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (6.3 g) in 81% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.75 (m, 2H), 8.34 (d, J=9.09 Hz, 1H), 4.20 (dd, J1=9.85 Hz, J2=6.82 Hz, 1H), 4.02-3.85 (m, 2H), 3.80 (d, J=10.11 Hz, 1H), 3.68 (m, 1H), 1.52-1.43 (m, 3H).
Reaction SMILES: [PH2:1]([OH:3])=[O:2].[C:4]([O:23][CH3:24])(=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(OOC(CC)(C)C)(CC)(C)C>[CH3:24][O:23][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([P:1]([OH:3])([CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:23][CH3:24])=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=[PH2]O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: CCC(C)(C)OOC(C)(C)CC
Product: CCCCCCCCCC(CCCCCCCC(=O)OC)P(=O)(O)C(CCCCCCCCC)CCCCCCCC(=O)OC
Temperature: 140 °C
Yield: 95.6 %

Procedure:
3.1 mL (0.03 moles) of 50% aqueous hypophosphorous acid and 16.92 g (0.06 moles) of methyl oleate (CE-1897 from P&G Chemical; iodine value=90) are mixed in a 100 mL single neck flask equipped with a distillation head. The mixture is purged with argon to remove oxygen and is heated under argon at 140° C. to remove water. After water is removed the mixture is cooled and 0.5 mL (0.0023 moles) of di-tert-amylperoxide are added and the mixture is purged with argon to remove oxygen and is heated under argon for 5 hours at 140° C. Tert-amyl alcohol is removed by distillation and 18.9 g (quantitative yield) of 9-{hydroxy-[1-(7-methoxycarbonyl-heptyl)-decyl]-phosphinoyl}-octadecanoic acid methyl ester (mixture of isomers) is obtained as a colorless wax melting near ambient temperature.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]3[CH2:12][CH2:13][CH2:14][C:9]3=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]CC)=O)=[CH:18][CH:17]=3)[CH:7]=2)=[CH:2]1.[NH3:28]>CO>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]=[C:10]3[CH2:12][CH2:13][CH2:14][C:9]3=[C:8]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([NH2:28])=[O:25])=[CH:20][CH:21]=3)[CH:7]=2)=[CH:2]1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Solvent: CO
Product: NC(=O)Cc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Yield: 50 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.065 g, 0.17 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL), followed by formation of the hydrochloride salt to afford the title compound (0.033 g, 50%) as a light yellow solid. MW=385.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.84 (s, 1H), 9.69 (s, 1H), 8.35-8.31 (m, 1H), 7.81-7.76 (m, 1H), 7.59-7.56 (m, 1H), 7.51 (s, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.05 (s, 1H), 6.92 (s, 1H), 3.43 (s, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.23 (quin, J=7.5 Hz, 2H); APCI MS m/z 350 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][C:7]#[N:8].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[Cl:12][C:11]1[C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])=[C:3]([CH3:13])[C:4]([O:5][CH2:6][C:7]#[N:8])=[CH:9][CH:10]=1
Reactant: Cc1c(OCC#N)ccc(Cl)c1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: Cc1c(OCC#N)ccc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3-amino-4-chloro-2-methylphenoxy)acetonitrile (4.76 g) was dissolved in pyridine (45 mL) under an atmosphere of nitrogen and cooled in an ice bath. Methanesulfonyl chloride (2.06 mL) was added dropwise, and then the mixture was allowed to stir overnight at room temperature. The reaction mixture was evaporated to dryness under reduced pressure to afford a residue which was flash chromatographed on silica and eluted with, first ethyl acetate:hexane (1:2), then with ethyl acetate:hexane (1:1) to afford 5.36 g as an 80:20 mixture of mono and bis mesylated product, respectively. This mixture was used in the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12][N:11]=1)([CH3:4])[CH3:3].C(O)C.C(=O)(O)[O-].[Na+].Cl.[NH2:33][OH:34]>C(OCC)(=O)C>[CH3:4][C:2]([Si:5]([CH3:22])([CH3:23])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20](=[NH:21])[NH:33][OH:34])[C:14]=2[CH:13]=[CH:12][N:11]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1nccc2c(C#N)cccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCc1nccc2c(C(=N)NO)cccc12
Temperature: 65 °C
Yield: 60.8 %

Procedure:
A round bottomed flask was charged with 1-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-5-isoquinolinecarbonitrile (D12; 417 mg, 1.28 mmol), ethanol (10 ml), sodium bicarbonate (107 mg, 12.8 mmol) and hydroxylamine hydrochloride (710 mg, 10.2 mmol). The vessel was fitted with a reflux condenser and warmed to 65° C. overnight. The resulting slurry was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo to give a yellow oil that was purified by flash column chromatography on silica using 0% to 100% ethyl acetate in cyclohexane as eluent. The relevant fractions were pooled and concentrated in vacuo to give the title compound as a yellow solid (280 mg).
Reaction SMILES: [CH2:1]([CH:4]([C:8](=O)[CH3:9])[C:5](=O)[CH3:6])[CH2:2][CH3:3].[C:11]([NH:14][NH2:15])([NH2:13])=[NH:12].[ClH:16]>CO.O.Cl>[ClH:16].[CH3:9][C:8]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]([CH3:6])[N:14]([C:11]([NH2:13])=[NH:12])[N:15]=1
Reactant: CCCC(C(C)=O)C(C)=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: CO
Solvent: O
Product: CCCc1c(C)nn(C(=N)N)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
A solution of 2.06 g of 3-propyl-2,4-pentanedione in 10 ml of methanol was added little by little to a solution of 1.56 g of aminoguanidine hydrochloride in 5 ml of water, 30 ml of methanol and 1 ml of concentrated hydrochloric acid, and stirred overnight at room temperature. The solvents were removed by distillation under reduced pressure, and the residue was purified by silica gel chromatography (eluent: chloroform/methanol=5/1) and then recrystallized from ethanol-ether to obtain 1.70 g of 3,5-dimethyl-4-propyl-1H-pyrazole-1-carboxamidine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[I:32])[C:27]#[N:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C(N=NC(N(C)C)=O)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:21][O:22][C:24]1[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][C:31]=1[I:32])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)CC(=O)OCc1ccccc1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](COc1cc(C#N)ccc1I)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.16 g (32.8 mmol) of benzyl (3R)-3-t-butoxycarbonylamino-4-hydroxybutanoate was dissolved in 100 ml of toluene. 10.5 g (42.7 mmol) of 3-hydroxy-4-iodobenzonitrile, 11.2 g (42.7 mmol) of triphenylphosphine and 7.4 g (42.7 mmol) of N,N,N′,N′-tetramethylazodicarboxamide were added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=O)[C:10]=2[C:11]=1[CH3:12].[OH:15][CH2:16][CH2:17][NH2:18]>>[OH:15][CH2:16][CH2:17][N:18]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:4])[C:10]=2[C:11]([CH3:12])=[C:2]([CH3:1])[C:3]1=[O:14]
Reactant: Cc1c2c(oc(=O)c1C)CCCC2=O
Reactant: NCCO
Product: Cc1c2c(n(CCO)c(=O)c1C)CCCC2=O

Procedure:
Prepared from 3,4-dimethyl-5,6,7,8-tetrahydro-cumarin- 5-one and 2-hydroxy-ethylamine at 130° C. over a period of 25 minutes.
Reaction SMILES: Cl[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[N+:13]([C:16]1[CH:17]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C(=O)([O-])O.[K+]>CCCCC(=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: ClCC1COc2ccccc2O1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCCCC(C)=O
Product: O=[N+]([O-])c1cccc(N2CCN(CC3COc4ccccc4O3)CC2)c1

Procedure:
A solution of 54.2 mmol (10 g) of 2-chloromethyl-2,3-dihydro-1,4-benzodioxin, 54.2 mmol (9.2 g) of 3-nitrophenylpiperazine and 6 g of potassium hydrogen carbonate in 100 ml of methyl-4-pentanone is heated at reflux for 72 hours. After cooling, the reaction mixture is concentrated. The residue is taken up in 200 ml of water and extracted with 200 ml of dichloromethane. The organic phase is dried over magnesium sulphate, concentrated and purified by chromatography on silica gel, using as eluant a 99/1/0.1 dichloromethane/methanol/ammonium hydroxide mixture, to yield the expected product.
Reaction SMILES: [NH2:1][C:2]([C@H:4]([NH:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11]Cl)[CH2:5][CH3:6])=[O:3].[OH-].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.C(Cl)(Cl)(Cl)Cl>[CH2:5]([C@@H:4]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:13])[C:2]([NH2:1])=[O:3])[CH3:6]
Reactant: CC[C@@H](NC(=O)CCCCl)C(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H](C(N)=O)N1CCCC1=O
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
6.2 g (0.03 mole) of (R)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide and 0.484 g (0.0015 mole) of tetrabutylammonium bromide are mixed in 42 ml of dichloromethane at 0° C. under a nitrogen atmosphere. 2.02 g (0.036 mole) of potassium hydroxide powder are added over 30 minutes at such a rate that the temperature of the reaction mixture does not exceed +2° C. The mixture is stirred for 15 minutes and then allowed to return to ambient temperature. The insoluble material is filtered off and the filtrate concentrated under reduced pressure. The residue obtained is stirred in 25 ml of carbon tetrachloride for 30 minutes, and then filtered off and dried. The product is recrystallized in 45 ml of ethyl acetate in the presence of 1.7 g of 0,4 nm molecular sieve. The latter is removed by hot filtration to give 3.85 g of (R)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide. Melting point: 116°-118° C. [alpha]D25 : +89.8° (c=1, acetone). Yield: 75.4%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)[CH:11]=1)#[N:9].[H][H]>O1CCOCC1.CCO.[Pd]>[NH2:9][CH2:8][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([O:17][C:18]2[CH:19]=[CH:20][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:11]=1
Reactant: Cc1nc(C#N)cc(Oc2ccc(CS(N)(=O)=O)cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1nc(CN)cc(Oc2ccc(CS(N)(=O)=O)cc2)n1
Temperature: 22 °C
Yield: 77 %

Procedure:
Combine triethylamine (117.83 mL) and palladium 10% on charcoal (20.10 g) to a solution of [4-(6-cyano-2-methyl-pyrimidin-4-yl)oxyphenyl]methanesulfonamide (67 g, 211.35 mmoles) in a mixture of 1,4-dioxane (469 mL) and EtOH (201 mL; 159.05 g) in a PARR reactor. Maintain the mixture at 22° C. Seal the reactor and pressurize it with hydrogen (400 PSI). Shake the reactor for 18 h while maintaining it at 22° C. Thereafter open the reactor and filter of the solids. Rinse the solid residue with MeOH (1 L), a mixture of dioxane/MeOH 1:1 (1 L), and MeOH (3×1 L). Collect and concentrate the filtrate to provide a solid, Collect and dry the solid in a vacuum oven, (45° C., 15 mbar) to provide the title compound as yellow solid, 62.41 g, 77% yield. MS (m/z): 309 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].Cl.Cl.[CH3:28][N:29]1[CH2:36][CH2:35][NH:34][CH2:33][C:30]21[CH2:32][CH2:31]2>>[F:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:34]4[CH2:33][C:30]5([CH2:32][CH2:31]5)[N:29]([CH3:28])[CH2:36][CH2:35]4)=[O:22])=[CH:18][N:17]=3)[C:14]=2[OH:15])[C:5]([CH3:25])=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: CN1CCNCC12CC2
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)N3CCN(C)C4(CC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-methyl-4,7-diazaspiro[2.5]octane dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.26-0.83 (m, 4 H) 2.41 (d, J=3.79 Hz, 6 H) 2.89 (br. s., 2 H) 3.40-3.91 (m, 4 H) 7.73 (d, J=7.07 Hz, 1H) 7.98 (d, J=11.87 Hz, 2 H) 8.20 (s, 1 H) 8.35-8.63 (m, 2 H); ESI-MS m/z [M+H]+ 447.3.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)[CH:7]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Product: O=C(c1ccc([N+](=O)[O-])cc1)n1cc(F)c(=O)[nH]c1=O
Yield: 52.8 %

Procedure:
2.6 g (0.02 mole) of 5-fluorouracil was reacted with 9.28 g (0.05 mole) of p-nitrobenzoyl chloride in the same manner as in Example 1 and 2.95 g (52.9% yield) of 5-fluoro-1-(p-nitrobenzoyl)uracil was obtained. The product was recrystallized from ethanol and white needles melting at 182°-183°C. were obtained. The results of an elementary analysis of the above crystals were well in agreement with the calculated value as follows:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C(F)(F)F)CCCC1=O
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at −10° C. After 30 minutes, 2-(trifluoromethyl)benzyl bromide (1.3 g, 5.2 mM) was added and the resultant mixture stirred at room temperature for 23 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo to afford 1.34 g (83%) of the 9-[(2-trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ 7.7 (d, 1H, J=8 Hz), 7.4-7.1 (m, 5H), 6.4 (d, 1H, J=8 Hz), 5.5 (s, 2H), 4.05 (s, 3H), 2.8 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1729 and 1656. MS (ES) m/e 402.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=O.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23]>>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[C:13]=1[CH2:20][C:21]1[C:22]([NH2:23])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[N:4][CH:3]=2
Reactant: Nc1cnccc1C=O
Reactant: COc1cccc(OC)c1CCC#N
Product: COc1cccc(OC)c1Cc1cc2ccncc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 3-amino-4-pyridine carboxaldehyde and 3-(2,6-dimethoxyphenyl)propionitrile
Reaction SMILES: [F:1][C:2]1[CH:39]=[CH:38][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[C:20]5=[N:19][C:18]=4[CH3:37])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:40]([O:44][C:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=[O:46])([CH3:43])([CH3:42])[CH3:41].C(N(C(C)C)CC)(C)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[F:1][C:2]1[CH:39]=[CH:38][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:50]6[CH2:51][CH2:52][N:47]([C:45]([O:44][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:46])[CH2:48][CH2:49]6)=[O:35])[C:20]5=[N:19][C:18]=4[CH3:37])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of Example 4 (200 mg, 0.37 mmol) in dichloromethane (10 mL), under argon, was treated with N-t-butoxycarbonylpiperazine (89.57 mg, 0.48 mmol) and diisopropylethylamine (77.42 μL 0.44 mmol). To the stirring solution, diethyl cyanophosphonate (72.06 μL, 0.43 mmol) was added. After stirring for two hours at room temperature, the reaction mixture was poured into water (20 mL) and the aqueous layer extracted with dichloromethane (three times 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mixture was used without further purification in the next step. (408 mg, ESI-MS (M+1) 709)