Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([C:9]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]>C(OCC)(=O)C>[C:5]([C:9]1[S:13][C:12]([N:14]=[C:1]=[O:2])=[N:11][N:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)c1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-t-butyl-2-amino-1,3,4-thiadiazole (10 grams) in ethyl acetate (300 ml) was added to the reaction vessel, and the resulting mixture was stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture was then purged with nitrogen gas to remove unreacted phosgene. The purged mixture was then filtered to recover the desired product 5-t-butyl-1,3,4-thiadiazol-2-yl isocyanate dimer as a solid having a melting point of 261° to 263° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8]C)=O.Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Cl)(C)C>C1COCC1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[CH2:4][CH2:5][C:6]([N:14]([O:15][CH3:16])[CH3:13])=[O:8]
Reactant: COC(=O)CCC(OC)OC
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(CCC(=O)N(C)OC)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
To a solution of methyl 4,4-dimethoxy-butyrate (4.99 g, 30.8 mmol) and N,O-dimethylhydroxylamine HCl (4.65 g, 47.68 mmol) in 60 mL of THF at −20° C., is added isopropylmagnesiumchloride (46 mL, 92.28 mmol, 2.0M in THF) maintaining the temperature below −20° C. After stirring at −10° C. for 30 min, the reaction mixture is quenched with 50 mL of water and extracted with 3×80 mL of EtOAc. The combined organic layers is dried over Na2SO4 and filtered through a short silica gel pluge. The solution is concentrated to give 4,4,N-Trimethoxy-N-methyl-butyramide (5.9 g, 99%) as pale liquid. M/Z=191.0
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[CH3:19][N:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][C:22]([CH3:28])=[N:21]1>>[CH3:19][N:20]1[C:24]([C:25]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:26])=[CH:23][C:22]([CH3:28])=[N:21]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccnc4[nH]c(=O)[nH]c34)c2)n(C)n1
Yield: 26 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride to afford the title compound (20 mg, 26%). 1H-NMR (δ, ppm, DMSO-d6): 2.19 (s, 3H, Mepyrrazole,3), 3.98 (s, 3H, Mepyrrazole,1), 6.48 (d, 1H, HPy,5, J=6.0 Hz), 6.81 (s, 1H, Hpyrrazole), 6.91 (d, 1H, Harom, J=8.0 Hz), 7.41 (t, 1H, Harom, J=8.0 Hz), 7.56 (s, 1H, Harom), 7.61 (d, 1H, Harom, J=8.0 Hz), 7.80 (d, 1H, HPy,6, J=6.0 Hz), 10.19 (s, 1H, NHamide), 11.19 (s, 1H, NHPy3), 11.39 (s, 1H, NHPy2). HRMS (EI): m/z [M+H] calcd for C18H17N6O3: 365.1362; found: 365.1356.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:10]1CC[CH2:12][CH2:11]1.[H-].[Na+].ICCO>CO.C(OCC)(=O)C>[N:1]1([CH2:12][CH2:11][OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1CCOC1
Reactant: c1ccc2[nH]cnc2c1
Agent: OCCI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: OCCn1cnc2ccccc21
Reaction time: 0.33 h

Procedure:
To a flask were added 2.3 g benzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 1.0 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 4.0 g 2-Iodoethanol were added and the mixture was heated to 50 C for 16 hours. The mixture was quenched slowly with 50 ml water, extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 25% methanol in ethyl acetate. A solid was obtained that was dissolved in a hot mixture of 10% methanol in ethyl acetate, cooled, filtered and dried giving 1.4 g white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[C:19]1([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:31])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3cc(N)cn3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Product: CC(=O)c1csc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)n1

Procedure:
Following general procedure B followed by C starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-phenyl-1,3-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.93 min; [M+H]+=394.01.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C[Sn](C)(C)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:12][C:4]1[CH:3]=[C:2]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: C[Sn](C)(C)c1ccccn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccccn2)cc1F
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a suspension of EXAMPLE 50A (5 g), Pd2(dba)3 (1.5 g) and tri-2-furylphosphine (1.5 g) in DMF (100 mL) was added 2-trimethylstannyl pyridine (9.5 g) and triethylamine (2 mL). The reaction mixture was stirred at 80° C. for 18 hours, cooled and partitioned between ethyl acetate and brine. The ethyl acetate layer was separated and concentrated, and the concentrate flash chromatographed on silica gel with 1:2 ethyl acetate/hexanes.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14](Br)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2.[C:18](=[O:21])([O-])[O-].[K+].[K+].O>N1C=CC=CC=1.[Cu](I)I>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[S:13][C:14]([O:21][C:18]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:15][CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C([O-])[O-]
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Br)s1
Agent: I[Cu]I
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccccc2)s1
Temperature: 125 °C
Reaction time: 65 h
Yield: 34.7 %

Procedure:
To a solution of (R)-N-(1-azabicyclo[2.2.2]oct-3-yl)(5-bromothiophene-2-carboxamide) (463 mg) in pyridine (10 mL) phenol (158 mg), copper iodide (32 mg) and potassium carbonate (97 mg) were added. The mixture was stirred at 125° C. for 65 h under nitrogen. Water was added and the aqueous layer was extracted with chloroform. Following evaporation, the residue was purified by flash chromatography using 5-20% 3.5M methanolic ammonia/chloroform mixtures as the eluent and then by reverse phase HPLC on a Waters Bondapak® C18 column using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. The free base was prepared by basification of the product-containing fractions and extraction into chloroform followed by evaporation to gave the title compound (80 mg); MS (ES+) 329 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=1)=[O:26])([CH3:21])[CH3:20])#[N:18].O>CN(C)C=O>[C:17]([C:19]([C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][CH:37]=1)[C:25]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:29]=1)=[O:26])([CH3:21])[CH3:20])#[N:18]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc([N+](=O)[O-])nc3)c2)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 66.7 %

Procedure:
To a solution of 5-bromo-2-nitropyridine (4.56 g, 22.4 mmol) and cesium carbonate (10.9 g, 33.6 mmol) in N,N-dimethylformamide (40 mL) was added dropwise a solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (6.92 g, 24.6 mmol) in N,N-dimethylformamide (20 mL) over 30 min, and the mixture was stirred at room temperature for 28 hr. Cesium carbonate (3.63 g, 11.2 mmol) was added to the reaction mixture, and the mixture was further stirred with heating at 60° C. for 15 hr. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate-hexane mixture (1:1, 200 mL, 3×50 mL). The combined organic layer was washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=90/10→50/50), and fractions containing the desired t product were concentrated under reduced pressure to give the title compound (6.01 g, 67%) as a yellow amorphous solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1.[CH2:12](B([O-])OC(C(C)(C)C)C)[CH:13]=[CH2:14].[F-].[Cs+]>O1CCCC1.C(OCC)C.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>[CH2:14]([C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([F:11])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: COc1cc(Br)cc(F)c1F
Reactant: C=CCB([O-])OC(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCc1cc(F)c(F)c(OC)c1

Procedure:
3.06 g of 1-bromo-3,4-difluoro-5-methoxybenzene (D2), 4.54 ml of pinacolyl allylboronate, 3.04 g of tetrakis(triphenylphosphine)palladium(0) and 7.62 g of caesium fluoride are suspended in 115 ml of tetrahydrofuran under an argon atmosphere. The reaction mixture is subsequently heated under reflux for 48 h. For work-up, the mixture is diluted with 400 ml of diethyl ether and extracted with 100 ml of water and 100 ml of saturated NaCl solution. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent: cyclohexane), giving 1.59 g of the title compound as a colourless oil; MS: 184.0 (M+); TLC: Rf=0.69 (cyclohexane/ethyl acetate 8:1 parts by volume).
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([S:14]C(=O)N(C)C)=[CH:6][C:5]=1C.[CH3:22]C(C[AlH]CC(C)C)C.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1>[C:10]([C:8]1([CH3:22])[CH:9]=[C:4]([CH2:3][OH:21])[CH:5]=[CH:6][CH:7]1[SH:14])([CH3:11])([CH3:12])[CH3:13]
Reactant: COC(=O)c1cc(C(C)(C)C)c(SC(=O)N(C)C)cc1C
Reactant: CC(C)C[AlH]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)C1(C)C=C(CO)C=CC1S
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 12.2 g (39.4 mmol) of 5-tert-butyl-4-dimethylcarbamoylsulfanyl-2-methyl-benzoic acid methyl ester (prepared in Example DDD) in toluene (140 mL) cooled to -78° C. under nitrogen was added 1.0 M DIBAL/CH2Cl2 (236.6 mL), dropwise over a 2.5 hour period. The reaction mixture was stirred an additional 30 minutes at -78° C. following addition, then at 0° C. for 1 hour. Saturated aqueous citric acid solution (approximately 600 mL) was added very slowly and carefully. The mixture was then extracted twice with EtOAc; the organic phases were combined, washed with brine, dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 1.47 (s, 9 H), 2.27 (s, 3 H), 3.57 (s, 1 H), 4.63 (s, 2 H), 7.06 (s, 1 H), 7.32 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[C:20]1(=[O:26])[NH:24][C:23](=[O:25])[CH:22]=[CH:21]1>C1(C)C=CC=CC=1.ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH:11]=[CH:12][CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:22]2[CH:21]1[C:20](=[O:26])[NH:24][C:23]2=[O:25])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1/C=C/C=C/c1ccccc1
Reactant: O=C1C=CC(=O)N1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C2C(c3ccccc3[N+](=O)[O-])C=CC(c3ccccc3)C12
Temperature: 130 °C

Procedure:
7.5 g (29.8 mmole) (E,E)-1-(2-nitrophenyl)-4-phenyl-1,3-butadiene and 2.9 g (29.9 mmole) maleic acid imide are heated in 10 ml toluene to 130° C. for 12 hours. After addition of 1.5 g (15.5 mmole) maleic acid imide it is heated at 130° C. for a further 24 hours. After cooling, it is diluted with 40 ml dichloromethane, the product filtered off, and crystallized from ethanol. One obtains 1,3,3a,4,7,7a-hexahydro-4-(2-nitrophenyl)-1,3-dioxo-7-phenyl-2H-isoindole in the form of pale yellow crystals, which decompose from 200°-208° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:21][CH:20]=1)[C:13]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=1)=[C:12]2[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[K+].[NH:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[CH:21][CH:20]=1)[C:13]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[CH:32][CH:31]=1)=[C:12]2[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCCl)cc2)c2ccc(OCc3ccccc3)cc12
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)n(Cc2ccc(OCCCN3CCCCC3)cc2)c2ccc(OCc3ccccc3)cc12

Procedure:
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4(3-chloro-propoxy)-benzyl]-3-methyl-1H-indole No. 164 (3 g, 5.1 mmol), potassium iodide (2.5 g, 15.3 mmol) and piperidine (3.0 mL, 30.6 mmol) were heated in DMF (30 mL) at 100° C. for 18 hours. The reaction was worked up by pouring into water and extracting with ethyl acetate. The organic layer was washed with water, brine and dried over magnesium sulfate. The solution was concentrated to an oil and the product precipitated out by adding methanol. The product was obtained as a white solid: Mp=104-106° C.; 1H NMR (DMSO) 7.47 (d, 4H, J=7.5 Hz), 7.38 (q, 4H, J=7.9 Hz), 7.36-7.30 (m, 1H), 7.28 (d, 2H, J=8.3 Hz), 7.19 (d, 1H, J=8.8 Hz), 7.12-7.10 (m, 4H), 6.80 (dd, 1H, J=8.8, 2.0 Hz), 6.72 (s, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.86 (t, 2H, J=6.4 Hz), 2.35-2.20 (m, 6H), 2.14 (s, 3H), 1.78-1.75 (m, 2H), 1.47-1.42 (m, 4H), 1.40-1.31 (m, 2H); MS eI m/z 650.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:4]([C:24]#[N:25])[CH:3]=1.[CH3:26]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:8][C:7]1[C:2]([CH3:26])=[CH:3][C:4]([C:24]#[N:25])=[C:5]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1Nc1cc(Cl)c(Br)cc1C#N
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: Cc1cc(C#N)c(N[C@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)cc1Cl
Temperature: 110 °C
Reaction time: 24 h

Procedure:
tert-Butyl {(1S,2S)-2-[(4-bromo-5-chloro-2-cyanophenyl)amino]cyclohexyl}carbamate, trimethyl boroxine and potassium carbonate were suspended in a mixed solvent of 1,4-dioxane (16 ml) and water (4 ml), tetrakis(triphenylphosphine)palladium was added thereto, followed by stirring at 110° C. for 1 day. By post-treating the reaction liquid, tert-butyl {(1S,2S)-2-[(5-chloro-2-cyano-4-methylphenyl)amino]cyclohexyl}carbamate was obtained.
Reaction SMILES: O1CCN(C(CCC(O)=O)=O)CC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:31]1[CH2:36][CH2:35][N:34]([C:37]([CH2:39][CH2:40][N:41]=[C:42]=[O:43])=[O:38])[CH2:33][CH2:32]1.[F:44][C:45]1[C:46](=[O:52])[NH:47][C:48](=[O:51])[NH:49][CH:50]=1>C1C=CC=CC=1.C(N(CC)CC)C>[O:31]1[CH2:32][CH2:33][N:34]([C:37]([CH2:39][CH2:40][NH:41][C:42]([N:49]2[CH:50]=[C:45]([F:44])[C:46](=[O:52])[NH:47][C:48]2=[O:51])=[O:43])=[O:38])[CH2:35][CH2:36]1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: O=C=NCCC(=O)N1CCOCC1
Agent: O=C(O)CCC(=O)N1CCOCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCNC(=O)n1cc(F)c(=O)[nH]c1=O)N1CCOCC1

Procedure:
The reaction of 3-morpholinocarbonylpropionic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 2-morpholinocarbonylethyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-(2-morpholinocarbonylethyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 4.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: CC1(C)CC(=O)Nc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)Nc2cc(OCCCCBr)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution (20 ml) of 7-hydroxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.4 g) in DMF were added 1,4-dibromobutane (0.75 ml) and potassium carbonate (0.35 g) and the mixture was stirred at 60° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→50:1) to give the title compound (0.6 g) as a colorless solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[C:15](=[O:28])[N:16]([CH2:25][CH2:26][CH3:27])[C:17](=[O:24])[N:18]([CH2:21][CH2:22][CH3:23])[C:19]=1[NH2:20].CCOC(/N=N/C(OCC)=O)=O>C(O)C.C(O)(=O)C>[CH2:25]([N:16]1[C:15](=[O:28])[C:14]2[NH:13][C:11]([C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)=[N:20][C:19]=2[N:18]([CH2:21][CH2:22][CH3:23])[C:17]1=[O:24])[CH2:26][CH3:27]
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(-c3ccc4c(c3)OCCO4)nc2n(CCC)c1=O
Temperature: 60 °C
Yield: 92.2 %

Procedure:
2.18 g (0.013 mol) of 1,4-benzodioxan-6-aldehyde, 80 ml of ethanol and 2.4 ml of glacial acetic acid are mixed together and 2.8 g (0.012 mol) of 5,6-diamino-1,3-dipropyluracil are added thereto. The clear solution is refluxed for 21/4 hours and then cooled to 60° C. At this temperature, 2.1 ml (0.013 mol) of diethylazodicarboxylate are added dropwise and the viscous suspension produced is mixed with 80 ml of ethanol and refluxed for 2 hours. After a further 20 hours at ambient temperature the mixture is cooled to 5° C., the solid matter is filtered under suction and washed with ethanol and ether. 4.1 g of the title compound are obtained in the form of a grey solid (=92% of theory), melting point 280°-282° C.
Reaction SMILES: C(C1C=C(NC2N=C(NC3C=CC=C(C(O)=O)C=3)C(F)=CN=2)C=CC=1)(O)=O.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[N:42]=[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([C:52]([O:54]C)=[O:53])[CH:45]=3)[C:40]([F:56])=[CH:39][N:38]=2)=[CH:32][C:31]=1[C:57]([O:59]C)=[O:58].[OH-].[Na+]>>[C:57]([C:31]1[CH:32]=[C:33]([NH:36][C:37]2[N:42]=[C:41]([NH:43][C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[C:46]([C:52]([OH:54])=[O:53])[CH:45]=3)[C:40]([F:56])=[CH:39][N:38]=2)[CH:34]=[CH:35][C:30]=1[O:29][CH3:28])([OH:59])=[O:58]
Reactant: COC(=O)c1cc(Nc2ncc(F)c(Nc3ccc(OC)c(C(=O)OC)c3)n2)ccc1OC
Agent: O=C(O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)O)c3)n2)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(C(=O)O)c3)n2)cc1C(=O)O
Yield: 103.8 %

Procedure:
In a manner analogous to the preparation of N2,N4-bis(3-carboxyphenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis[4-methoxy-3-(methoxycarbonyl)phenyl]-5-fluoro-2,4-pyrimidinediamine (80 mg, 0.18 mmol) and NaOH (200 mg, 5 mmol) gave N2,N4-bis(3-carboxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine (80 mg). 1H NMR (DMSO-d6): δ 3.75 (s, 3H), 3.80 (s, 3H), 6.94 (d, J=9.6 Hz, 1H), 7.05 (d, J=9.3 Hz, 1H), 7.78-7.80 (m, 3H), 7.94 (dd, J=9.3 Hz, 1H), 8.04 (d, J=3.6 Hz, 1H), 9.10 (s, 1H, NH), 9.30 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): 6-165.56; LCMS: ret. time: 14.65 min.; purity: 100%; MS (m/e): 428.83 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.Cl>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCC2)c(Br)c1

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2, 1 g, 2.53 mmol), pyrrolidine (0.544 g, 5.06 mmol), DIPEA (1.325 mL, 7.58 mmol) and iPrOH (2.53 mL) were added to a MW vial and subjected to MW irradiation at 140° C. for 1 h. The mixture was treated with aqueous HCl (40 mL of 0.5 M) was added and extracted with EtOAc The combined extracts were washed with 0.5 M HCl (40 mL) and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue was crystallized from cyclohexane/EtOAc to yield the title compound as an off-white solid. UPLC-MS (Condition 3) tR=1.34 min, m/z=430.1/432.1 [M+H]+, m/z=428.3/430.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.76-2.01 (m, 4H) 3.60-3.80 (m, 4H) 7.33 (d, J=8.20 Hz, 2H) 7.72-7.91 (m, 2H) 8.32 (d, J=1.95 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H) 10.20 (s, 1H).