Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[C:13]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([N:27]2[N:31]=[C:30]3[C:32](Br)=[CH:33][CH:34]=[C:35](Br)[C:29]3=[N:28]2)[C:18]=1[OH:38])([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6]([C:32]2[C:30]3[C:29](=[N:28][N:27]([C:19]4[CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]=4[OH:38])[N:31]=3)[C:35]([C:6]3[CH:7]=[CH:8][C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][CH:5]=3)=[CH:34][CH:33]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)c1cc(-n2nc3c(Br)ccc(Br)c3n2)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CN(C)c1ccc(-c2ccc(-c3ccc(N(C)C)cc3)c3nn(-c4cc(C(C)(C)C)cc(C(C)(C)C)c4O)nc23)cc1
Temperature: 95 °C

Procedure:
To a 40 mL glass vial, was added 4-(dimethylamino)phenylboronic acid (0.0858 g, 0.520 mmol), 2,4-di-tert-butyl-6-(4,7-dibromo-benzotriazol-2-yl)-phenol (0.1251 g, 0.260 mmol), toluene (0.65 mL), phase transfer catalyst (Aliquat 366®, 60% in toluene, 0.35 mL), tetrakis (triphenylphosphine) palladium in toluene (0.0104 M, 1.0 ml), and 0.8 mL of 2M degassed aqueous potassium carbonate. The vial was heated on an orbital shaker at 95° C. for 20 hours. After cooling to room temperature, methanol was added to the reaction mixture. Yellow crystals of product were collected after filtration and washed with DI water. Photoluminescence spectrometry of a dilute solution of the product in dichloromethane showed strong emission centered at 569 nm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1.[H-].[Na+].F[C:22]1[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([CH3:28])[CH:27]=1>CN(C)C=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:22]2[CH:23]=[CH:24][C:25]([N+:29]([O-:31])=[O:30])=[C:26]([CH3:28])[CH:27]=2)=[C:12]([CH:16]([CH3:18])[CH3:17])[O:11][N:10]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (500 mg, 1.79 mmol) in dimethylformamide (6 mL) at 0° C. was treated with sodium hydride (60% dispersion in oil, 72 mg, 1.8 mmol) and was maintained for 15 minutes before the addition of 5-fluoro-2-nitrotoluene (182 μL, 1.5 mmol). The reaction was then allowed to stir at ambient temperature for 16 h. The product was extracted by partitioning the mixture in diethyl ether (50 mL) and water (50 mL). The aqueoues phase was extracted with diethyl ether (3×50 mL) then the organics were combined and washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and and concentrated to yield a crude oil. The product was purified by column chromatography on silica gel eluting with 20% ethyl acetate/hexanes. Yield=379 mg (60%) of 3-(2,6-dichlorophenyl)-5-isopropyl-4-[(3-methyl 4nitrophenoxy)methyl]-isoxazole.
Reaction SMILES: O.NN.[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[Cl:32][C:33](Cl)(Cl)[C:34]#[N:35].Cl>CS(C)=O.[Cu]Cl>[Cl:32][C:33]([C:34]#[N:35])=[CH:4][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cl[Cu]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=C(Cl)C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.6 %

Procedure:
To a solution of hydrazine hydrate diluted in 16 ml of dimethylsulfoxide under argon are added dropwise a solution of 4.76 g (16.41 mmol) of tert-butyl 4-(4-formylphenyl)piperazine-1-carboxylate dissolved in 32 ml of dimethylsulfoxide. The reaction mixture is stirred at room temperature for 3 h before being cooled over an ice bath. Then, the successive addition is made of 11.45 ml (82 mmol) of triethylamine, 162 mg of copper (I) chloride and, in 5 min, a solution of 8.23 ml (82 mmol) of trichloroacetonitrile diluted in 16 ml of dimethylsulfoxide. The reaction mixture is stirred at room temperature for 18 h then poured onto an aqueous 0.1N hydrochloric acid solution. The product is extracted several times with dichloromethane. The organic phases are combined, dried over magnesium sulfate, and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 8:2) to yield 1.52 g (26%) of tert-butyl 4-(4-(2-chloro-2-cyanovinyl)phenyl)piperazine-1-carboxylate in the form of a yellow solid (mixture of the two isomers Z/E).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:13]([B-](F)(F)F)([CH3:15])=[CH2:14].[K+].C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=C(S([O-])(=O)=O)C=2OC)CCCCC1.[Na+]>C(O[Pd]OC(=O)C)(=O)C.O1CCOCC1.O>[CH2:14]=[C:13]([C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH3:15]
Reactant: CCOC(=O)c1cccc(Cl)n1
Reactant: C=C(C)[B-](F)(F)F
Agent: CC(=O)O[Pd]OC(C)=O
Agent: COc1ccc(S(=O)(=O)[O-])c(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)c1cccc(C(=O)OCC)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A first flask was charged with 1,4-dioxane/H2O (50 mL/10 mL). The flask was cooled to 0° C. and vacuum was applied for 20 minutes. A second flask was charged with ethyl 6-chloropicolinate (4.200 g, 22.63 mmol), potassium isopropenyltrifluoroborate (4.353 g, 29.42 mmol), K2CO3 (4.378 g, 31.68 mmol), diacetoxypalladium (0.1524 g, 0.6789 mmol) and sodium 2′-(dicyclohexylphosphino)-2,6-dimethoxybiphenyl-3-sulfonate (0.6959 g, 1.358 mmol). The flask was also evacuated with vacuum and back filled with N2 three times. The cold degassed dioxane/H2O solution was added to the second flask, which was evacuated with vacuum and back filled with argon five times. The reaction mixture was then heated to 80° C. for 3 hours. The reaction was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was diluted with EtOAc (200 mL), washed with saturated NaHCO3, dried (Na2SO4) and concentrated to give the desired product, which was used without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:9]=1.[F:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])[C:45]=1[C:51]1[CH:56]=[CH:55][C:54](B2OC(C)(C)C(C)(C)O2)=[CH:53][N:52]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][Si:2]([CH3:42])([CH3:41])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:54]3[CH:53]=[N:52][C:51]([C:45]4[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=4[F:43])=[CH:56][CH:55]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:24][CH:23]3[N:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Reactant: CC1(C)OB(c2ccc(-c3c(F)cccc3F)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5c(F)cccc5F)nc4)c3n1)C2
Temperature: 95 °C
Yield: 50.3 %

Procedure:
tert-Butyl 3-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate (1.26 g, 1.73 mmol), 2-(2,6-difluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.88 g, 2.1 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (141 mg, 0.173 mmol), and potassium carbonate (0.716 g, 5.18 mmol) were placed in a 100-mL round bottom flask equipped with a reflux condenser and rubber septa. Then, the reaction vessel was evacuated and back filled with nitrogen 3 times before adding 1,4-dioxane (3.50 mL) and water (0.933 mL). Then, the reaction was sparged with nitrogen for 8 minutes, then maintained under nitrogen with a balloon and heated at 95° C. for 6 hr. The reaction mixture was then cooled to ambient temperature, diluted with dichloromethane (100 mL), filtered through a plug of Magnesol (ca. 60 mL). and the filtrate was concentrated. The crude product was purified by flash chromatography, (0 to 10% ethylacetate/dichloromethane) to afford the title compound (690 mg, 50%) as an ivory foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[C:29](F)(F)C(O)=O.C=O.C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][N:25]([CH3:29])[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3cnc(NCC4CCNCC4)nc23)cc1Cl
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[4-piperidinylmethylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid and subsequent reductive amination with formaldehyde and sodium cyanoborohydride. Melting point: 198°-201° C.; Rf : 0.65 (alumina; methylene chloride/methanol=20:1)
Reaction SMILES: [C:1]([C:3]1[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8])#[N:2].B(Br)(Br)Br>ClCCl>[C:1]([C:3]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8])#[N:2]
Reactant: COc1ccc(OCC(=O)Nc2ccc(Cl)cn2)c(C#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cc(O)ccc1OCC(=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 26 h
Yield: 44.5 %

Procedure:
To the suspension of (2-cyano-4-methoxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide (40.0 g) obtained in Reference Example 59 in dichloromethane (2000 ml), boron tribromide (173 g) is added at −58° C. dropwise over 40 minutes. The reaction solution is stirred for 26 hours with keeping the internal temperature between −20° C. and 0° C., and then poured to an ice-water. The precipitated solid is collected by filtration, washed with water, and then dried under reduced pressure. A part of the resulting solid (37.2 g), i.e. 24.3 g thereof is purified by silica gel column chromatography (eluent: chloroform/methanol=50/1-10/1) to give the title compound (17.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([F:24])[CH:19]=3)=[N:16][CH:17]=2)=[O:9])=[N:6][CH:7]=1.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[F:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([CH2:11][NH:10][C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]4=[O:25])=[CH:3][CH:4]=3)=[O:9])=[CH:17][N:16]=2)[CH:23]=[CH:22][N:21]=1
Reactant: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(Br)cn1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(-n2ccccc2=O)cn1
Temperature: 108 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-N-42′-fluoro-[2,4′-bipyridin]-5-yl)methyl)picolinamide 38-4 (38.6 mg, 0.1 mmol), 2-hydroxypyridine 44-1 (19.0 mg, 0.2 mmol), CuI (9.5 mg, 0.05 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (7.1 mg, 0.05 mmol) and K2CO3 (28 mg, 0.20 mmol) in toluene (0.6 mL) was stirred at 108° C. for 8 hours. After cooling to room temperature, the mixture was filtered through celite (washed with ethyl acetate) and the filtrate was concentrated with rotavap. The residue was subjected to preparative reverse phase HPLC separation to give N-42′-fluoro-[2,4′-bipyridin]-5-yl)methyl)-2-oxo-2H-[1,3′-bipyridine]-6′-carboxamide 44 as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][O:30]2)[C:3]1=[O:35].[Li+].CC([N-]C(C)C)C.[F:44][C:45]([F:55])([F:54])[C:46]1[CH:53]=[CH:52][C:49]([CH:50]=[O:51])=[CH:48][N:47]=1>C1COCC1.C(Cl)Cl.O>[OH:51][CH:50]([C:49]1[CH:48]=[N:47][C:46]([C:45]([F:55])([F:44])[F:54])=[CH:53][CH:52]=1)[C:11]1[C:6]2[C:5](=[O:24])[N:4]([CH2:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[C:3](=[O:35])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:21])([F:22])[F:23])[CH:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(OC(F)(F)F)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)nc3)c(Oc3cccc(OC(F)(F)F)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of 1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (156 mg, 0.32 mmol) in THF (6 mL) at −78° C. was added LDA (0.8 mL, 1.6 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 6-(trifluoromethyl)nicotinaldehyde (112 mg, 0.64 mmol) in THF (3 mL) was added dropwise. The reaction was stirred at −78° C. for 45 min then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:6) to give 5-(hydroxy(6-(trifluoromethyl)-pyridin-3-yl)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethoxy)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (40 mg, 18.6% yield) as a solid. LCMS: [M+-THP-OH—H] 569 and TR=2.162 min.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:28])[NH:14][C:15]1[CH:16]=[C:17]([C:21]2[N:22]([CH3:27])[N:23]=[N:24][C:25]=2[SH:26])[CH:18]=[CH:19][CH:20]=1)([O:6]CC)=[O:5])C>Cl>[P:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:28])[NH:14][C:15]1[CH:16]=[C:17]([C:21]2[N:22]([CH3:27])[N:23]=[N:24][C:25]=2[SH:26])[CH:18]=[CH:19][CH:20]=1)([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CCCNC(=O)Nc1cccc(-c2c(S)nnn2C)c1)OCC
Agent: Cl
Product: Cn1nnc(S)c1-c1cccc(NC(=O)NCCCP(=O)(O)O)c1

Procedure:
80 ml of 12N hydrochloric acid was added to 2.0 g of 4-[3-{3-(3-phosphonopropyl)ureido}phenyl]-3-methyl-5-mercaptotriazole (9) thus obtained. The system was allowed to undergo reaction at a temperature of 90° C. over 8 hours. After the completion of the reaction, hydrochloric acid was distilled off under reduced pressure. 20 ml of water was added to the system. The system was then dissolved under heating. Sodium chloride was gradually added to the solution to deposit crystals. The addition of sodium chloride continued until the solution was somewhat whitened. The solution thus whitened was then heated so that it was homogenized. The solution was naturally filtered, and then allowed to stand. As a result, a crystalline 4-[3-{3-(3-phosphonopropyl)ureido}phenyl]-3-methyl-5-mercaptotriazole (10) was deposited. (Yield: 0.58 g (33%); m.p. 195° C.)
Reaction SMILES: O=[C:2]([CH3:8])[C:3](=O)[C:4]([OH:6])=[O:5].CC[O-].[Na+].[CH3:13][S:14][C:15](=[NH:17])[NH2:16]>>[CH3:13][S:14][C:15]1[N:17]=[C:3]([C:4]([OH:6])=[O:5])[CH:2]=[CH:8][N:16]=1
Reactant: CC(=O)C(=O)C(=O)O
Reactant: CSC(=N)N
Agent: CC[O-]
Agent: [Na+]
Product: CSc1nccc(C(=O)O)n1

Procedure:
In step a of scheme 1, reaction of the ketone with diethyl oxalacetate in the presence of a base, such as sodium ethoxide, and an organic solvent such as ethanol, provides the dioxobutanoic acid. Refluxing the dioxobutanoic acid, in step b, in the presence of a base, such as EtONa, and 2-methylisothiourea followed by and organic extraction and acid wash provides the 2-(methylthio)pyrimidine-4-carboxylic acid. In step c, the carboxylic acid is converted to the amide using standard amine coupling methodologies, such as with PyBOP or EDC, in the presence of the appropriate amine, e.g., NHRcRd. In step d, oxidation of the thiol with an oxidizing agent such as m-CPBA or H2O2 in CH3CO2H provides the sulfinyl or sulfonyl compound. In step e, reaction of the sulfinyl or sulfonyl compound with the appropriate amine, HNRaRb, in an organic solvent such as dioxane provides the compound of formula I.
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].CN(C)C=O>C(N(CC)CC)C>[O:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][CH:10]1[CH2:9][N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: N#CCCCBr
Reactant: c1ccc(CNCC2CCc3ccccc3O2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.6 %

Procedure:
A mixture of 12.5 g of 3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine, 9 g of 4-bromobutanenitrile, 200 ml of N,N-dimethylformamide and 10 ml of N,N-diethylethanamine was stirred for 72 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between 1,1'-oxybisethane and water. The organic layer was separated, dried, filtered and evaporated, yielding 11 g (68.7 % ) of (±)-4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]butanenitrile (interm. 53).
Reaction SMILES: [C:1]1([C:7]2([N:13]=[N+]=[N-])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCOCC1>[C:1]1([C:7]2([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NC1(c2ccccc2)CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: NC1(c2ccccc2)CCCCC1
Temperature: 0 °C

Procedure:
The crude azide (18.0 g, ≤96 mmol) was dissolved in dioxane (300 mL) with triphenylphosphine (40 g, 152 mmol) and the stirred solution was refluxed for 4 h. under N2 (g) before adding H2O (9 mL, 0.5 mol). After about 46 h. further reflux, solvent was removed in vacuo at about 45-50° C. and residual moisture was removed by azeotropic distillations in vacuo with CH3CN and Et2O, respectively. The syrupy residue was dissolved in boiling Et2O and chilled to about 0° C. for about 16 h. Precipitated Ph3PO was removed by filtration, and 1M HCl in Et2O (90 mL) was added dropwise at about 5° C. to the etherol filtrate to precipitate the desired 1-phenyl-cyclohexylamine as its HCl salt (12.7 g, LC-MS m/z 162 (MH+)) which was recrystallized from CHCl3 /i-Pr2O before use.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16])=[O:12])=O)(C)(C)C.BrC[C:33]1[CH:41]=[CH:40][C:36]2=[N:37][O:38][N:39]=[C:35]2[CH:34]=1.C1CCNCC1.CO>C(Cl)(Cl)Cl.C(#N)C>[NH2:8][C:9]1[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]([NH:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([C:33]2[CH:41]=[CH:40][C:36]3=[N:37][O:38][N:39]=[C:35]3[CH:34]=2)[CH2:23][CH2:24]1)=[O:16])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCNCC1
Reactant: BrCc1ccc2nonc2c1
Solvent: CO
Solvent: CC#N
Solvent: C1CCNCC1
Product: Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(c2ccc3nonc3c2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[{N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl}aminomethyl]piperidine (0.050 mmol), 5-(bromomethyl)benzo[c]furazan (0.75 mmol), (piperidinomethyl)polystyrene (2.6-2.8 mmol/g, 60 mg, 0.15 mmol), methanol (0.2 mL), acetonitrile (1.0 mL), and chloroform (0.50 mL) was stirred at 50° C. overnight. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. To the resulting mat(rial were added chloroform (1.5 mL) and phenyl isocyanate (0.075 mL) and the solution was stirred at room temperature for 1 h, loaded onto Varian™ SCX column, and washed with CH3OH (5 mL×2). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated. The residue was dissolved in methanol (1 mL) and 4 N HCl in dioxane (0.50 mL) was added. The solution was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto Varian™ SCX column, washed with CH3OH (5 mL×2), and eluted off using 2 N NH3 in CH3OH (5 mL). Concentration and preparative TLC (SiO2, ethyl acetate/MeOH=5/1) afforded 4-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(benzo[c]furazan-5-yl)piperidine (Compound No. 2130) (3.6 mg, 16%): The purity was determined by RPLC/MS (87%); ESI/MS m/e 459.3 (M++H, C22H24F2N6O3).
Reaction SMILES: [Br:1]Br.C(Cl)(Cl)Cl.[O:7]=[C:8]([CH2:14][CH3:15])[CH2:9][C:10]([O:12][CH3:13])=[O:11]>>[Br:1][CH:14]([CH3:15])[C:8](=[O:7])[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCC(=O)CC(=O)OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: COC(=O)CC(=O)C(C)Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of bromine (8.61 mL, 167 mmol) in chloroform (20 mL, 200 mmol) was added dropwise over a period of 2 h to a solution of 3-oxopentanoic acid, methyl ester (Aldrich, 21.0 mL, 167 mmol) in chloroform (147 mL, 1840 mmol), at 0° C. (ice bath). The reaction mixture was stirred for 30 min at 0° C. and then allowed to stand at room temperature overnight. While stirring, a stream of air was bubbled through the solution for 1 hour. After drying over sodium sulfate, the solvent was evaporated under reduced pressure leaving the desired compound.