Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH3:11])=[O:7])=[C:4]([F:14])[CH:3]=1.[NH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18].C([O-])([O-])=O.[K+].[K+].C(C1CCCCC1=O)(=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.[Cu]I.O>[CH2:9]([NH:8][C:6]([C:5]1[CH:12]=[CH:13][C:2]([NH:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:3][C:4]=1[F:14])=[O:7])[CH2:10][CH3:11]
Reactant: CC(C)(N)C(=O)O
Reactant: CCCNC(=O)c1ccc(Br)cc1F
Agent: [Cu]I
Agent: CC(=O)C1CCCCC1=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Temperature: 100 °C
Yield: 148.2 %

Procedure:
The title compound, made in accordance with General Method 3, may be used to prepare compound 5 in accordance with General Method 1. 4-Bromo-2-fluoro-N-propylbenzamide (620 mg, 2.39 mmol), 2-aminoisobutyric acid (422 mg, 4.09 mmol), CuI (100 mg, 0.6 mmol), TEA (catalytic amount) and K2CO3 (1.13 g, 8.1 mmol) were dissolved in DMF (8 mL) and water (2 mL) stirred at RT for 5 min. 2-Acetylcyclohexanone (0.13 g, 0.3 mmol) was added and the reaction mixture was heated at 100° C. for 18 h. The reaction mixture was acidified with 1 M citric acid (pH 4) and extracted with ethyl acetate (100 mL, 2 times). The combined organic layer was dried over Na2SO4 and concentrated to obtain 1.0 g of 2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid.
Reaction SMILES: N1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH:22]4[C:31]5[C:26](=[C:27]([C:32]#[N:33])[CH:28]=[CH:29][CH:30]=5)[O:25][CH2:24][CH2:23]4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][CH:7]=2)C=NN=N1.C(C1C2C(=C(C#N)C=CC=2)OCC1)=O.O=C(N1CCNCC1)CC1C=CC2[C:55](=[O:58])[O:56][CH2:57]C=2C=1>>[O:58]=[C:55]1[C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH:22]4[C:31]5[C:26](=[C:27]([C:32]#[N:33])[CH:28]=[CH:29][CH:30]=5)[O:25][CH2:24][CH2:23]4)[CH2:17][CH2:16]3)=[O:14])=[CH:8][C:7]=2[CH2:57][O:56]1
Reactant: N#Cc1cccc2c1OCCC2CN1CCN(C(=O)Cc2ccc(-n3cnnn3)cc2)CC1
Reactant: O=C1OCc2cc(CC(=O)N3CCNCC3)ccc21
Agent: N#Cc1cccc2c1OCCC2C=O
Product: N#Cc1cccc2c1OCCC2CN1CCN(C(=O)Cc2ccc3c(c2)COC3=O)CC1

Procedure:
4-({4-[(1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetyl]piperazin-1-yl}methyl)-3,4-dihydro-2H-chromene-8-carbonitrile was prepared in an analogous fashion to that described for the synthesis of 4-[(4-{[4-(1H-tetrazol-1-yl)phenyl]acetyl}piperazin-1-yl)methyl]-3,4-dihydro-2H-chromene-8-carbonitrile above starting from 4-formyl-3,4-dihydro-2H-chromene-8-carbonitrile and 5-[2-oxo-2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one. 1H-NMR (400 MHz, CDCl3) δ ppm 7.85 (d, J=7.8 Hz, 1H), 7.31˜7.38 (m, 4H), 6.8 (t, J=7.8 Hz, 1H), 5.24 (s, 2H), 4.15˜4.45 (m, 2H), 3.8 (s, 2H), 3.4˜3.73 (m, 4H), 2.88˜2.95 (m, 1H), 2.3˜2.52 (m, 6H), 1.97˜2.1 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[CH2:21](I)[CH3:22].[OH-].[K+]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:21][CH3:22])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1CC

Procedure:
In analogy to the procedure described for example 2 a], 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (PCT Int. Appl. (2003), WO 2004000785 A2) was reacted with ethyl iodide in the presence of potassium hydroxide to to give 2-ethyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1>CCO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=1
Reactant: COCCOCCOCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: COCCOCCOCCOc1ccc(N)cc1
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a stirred solution of 17 (1.39 g, 4.86 mmol) in acidic EtOH (5 mL) in a Parr apparatus was added a catalytic amount of 20% Pd/C (0.05 g). The reaction vessel was purged with H2 then pressurized to 70 psi. After stirring for 16 h the reaction mixture was filtered through a 4 cm pad of celite and concentrated under reduced pressure to afford 18 as a brown oil (1.24 g, 100%): 1H NMR (300 MHz, CDCl3) δ 6.75 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H), 4.11-3.99 (m, 2H), 3.87-3.78 (m, 2H), 3.76-3.51 (m, 8H), 3.42 (s, 1H), 3.38 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+]>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: Nc1nc(Nc2ccccc2)nc2c1ncn2Cc1ccccc1
Yield: 88.7 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (100 mg, 0.385 mmol) and aniline (359 mg, 3.85 mmol) in 1-butanol (10 ml) were refluxed on heating for 20 hours. The reaction mixture was condensed in vacuo. To the residue was added 5N aqueous sodium hydroxide and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate, filtered and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (108 mg, yield 89%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[CH:10][C:9]([CH2:17][CH2:18][CH:19]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[CH3:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:30][CH2:31][N:32]([CH2:19][CH2:18][CH2:17][C:9]3[CH:10]=[C:11]([C:12]4[S:13][CH:14]=[CH:15][CH:16]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:33][CH2:34]2)[CH:25]=[CH:26][C:27]=1[CH3:28]
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: O=CCCc1cc(-c2cccs2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4cccs4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
54 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)-propanal (40 mg, 0.142 mmol), 1-(3,4-dimethylphenyl)piperazine (27 mg, 0.142 mmol), DIPEA (0.040 mL, 0.213 mmol) and NaBH(OAc)3 (90 mg, 0.573 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5](C2C=NN(C3CCN(C(OC(C)(C)C)=O)CC3)C=2)=[N:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=2[N:12]=1.NC1C(C(O)=[O:44])=NC=CN=1.NC1C=CC(F)=CC=1O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:7]([C:8]([NH:12][C:11]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=2[OH:9])=[O:44])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4nc5ccc(F)cc5o4)n3)cn2)CC1
Reactant: Nc1nccnc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccc(F)cc1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1nccnc1C(=O)Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The tert-butyl 4-[4-[5-amino-6-(6-fluoro-1,3-benzoxazol-2-yl)pyrazin-2-yl]pyrazol-1-yl]piperidine-1-carboxylate used as starting material was prepared as follows: 3-aminopyrazine-2-carboxylic acid (5 g) and 2-amino-5-fluoro-phenol (5.94 g) were dissolved in DMF (30 ml). Triethylamine (5.81 g) and HATU (19.13 g) were added to the solution. The resulting mixture was stirred at room temperature for 24 hours, diluted with ethyl acetate (100 ml) and washed with brine (3×20 ml). The organic layer was dried over sodium sulfate. The precipitate was collected, recrystallized in ethanol and further purified by chromatography on silica gel (hexane/ethyl acetate/Methanol) to give 3-amino-N-(4-fluoro-2-hydroxy-phenyl)pyrazine-2-carboxamide (6 g). NMR Spectrum: (400 MHz, DMSOd6) 10.8 (s, 1H), 10.2 (s, 1H), 8.30 (m, 2H), 7.80 (s, 1H), 7.50 (br, 2H), 6.60 (m, 2H). Mass spectrum: M+H+ 249.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]4[O:26][C:27](=S)[N:28]=[C:22]4[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:28][C:27]([NH:35][CH:31]4[CH2:34][CH2:33][CH2:32]4)=[O:26])[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCC1
Reactant: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccn4oc(=S)nc4c3)C(C)(C)C2=O)cc1
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(NC(=O)NC4CCC4)c3)C(C)(C)C2=O)cc1

Procedure:
This compound may be prepared as obtained in stage c) of Example 9, but starting with 200 mg of 3-(4-tert-butylphenyl)-5,5-dimethyl-1-[(2-thioxo-2H-[1,2,4]oxadiazolo[2,3-a]pyridin-7-yl)methyl]imidazolidine-2,4-dione obtained in stage b) of Example 9, 4 mL of dioxane and 40.2 mg of cyclobutanamine. After chromatography on a column of silica, eluting with a mixture of heptane/ethyl acetate (gradient from 100/0 to 0/100 by volume), 112.6 mg of 1-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)-3-cyclobutylurea are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]3[C:15]2=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc(CCCN)cc1OC
Solvent: CC(=O)O
Product: COc1ccc(CCCN2C(=O)c3ccccc3C2=O)cc1OC

Procedure:
6.4 g of 3-(3,4-dimethoxyphenyl)-propylamine (0.03 moles) was refluxed with 5.47 g of phthalic anhydride (0.037 moles) in 70 ml of acetic acid for 2.5 hours. The solvent was then removed in the rotary evaporator. Recrystallization of the residue from 150 ml of ether gave 4.0 g of a first crop, m.p. 82°-85° and 7.0 g of a second crop, m.p. 81°-83°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.[OH-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[C:13](=[N:20][C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[CH:12]=2)[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)c(N=c2cc(-c3ccc(O)c(O)c3)n(C)c(=O)n2C)c(C)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)pyrimidinone (5.0 g) in aqueous hydrobromic acid (47%) (50 ml) was refluxed for 1.5 hours. After being cooled to ambient temperature, the solution was neutralized with aqueous sodium hydroxide, and extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The resulting oil was crystallized from a mixture of diisopropyl ether and ethyl acetate (1:1 v/v) to give 3,4-dihydro-6-(3,4-dihydroxyphenyl)-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (4.41 g).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:20])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])=[N:10][C:5]2=[CH:4][CH:3]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[NH3:34].[Cl-].[NH4+]>C(CC(=O)C)(=O)C.[Cu+2].CN1C(=O)CCC1>[NH2:34][C:3]1[CH:4]=[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17][CH2:18][CH3:19])[N:8]([CH3:20])[C:6]2=[N:7][CH:2]=1
Reactant: CCSc1ccccc1-c1nc2ccc(Br)nc2n1C
Reactant: N
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC(=O)CC(C)=O
Solvent: CN1CCCC1=O
Product: CCSc1ccccc1-c1nc2cc(N)cnc2n1C
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a pressure-resistant reaction container, 5-bromo-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (1.74 g), copper (II) acetylacetone (0.26 g), acetylacetone (0.50 g), cesium carbonate (3.25 g), NMP (9 ml), and 28% of aqueous ammonia (4 ml) were added, and stirred at 120° C. for 6 hours. The mixture was cooled to room temperature, and then saturated aqueous ammonium chloride solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 1.20 g of 6-amino-2-(2-ethylsulfanylphenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 125).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)([CH3:7])[CH3:6])[CH3:2].[OH-].[K+].CS(C)=O.Br[CH2:26][CH2:27][CH2:28][Cl:29]>O>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:26][CH2:27][CH2:28][Cl:29])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc2[nH]ccc12
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc2c1ccn2CCCCl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
2-(1H-Indol-4-yloxy)-2-methylpropionic acid ethyl ester (0.100 g, 0.40 mmol, 1.0 eq), powdered potassium hydroxide (0.034 g, 0.61 mmol, 1.5 eq), and DMSO (3 mL) were mixed and stirred at room temperature for 10 minutes. 1-Bromo-3-chloropropane (0.12 mL, 0.191 g, 1.21 mmol, 3.0 eq) was then added to the above mixture. The reaction mixture was stirred at room temperature for another 1.5 hours before 15 mL of water was added. The mixture was extracted with ethyl acetate (2×30 mL). The organic layer was collected, combined, washed with water (6×25 mL) and brine (2×20 mL), and dried over anhydrous Na2SO4. The solvent was removed in vacuo to afford 2-[1-(3-chloropropyl)-1H-indol-4-yloxy]-2-methylpropionic acid ethyl ester (0.127 g, yield: 97%) as a dense oily liquid, which was used for the next step without further purification.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:13][C:14]1[C:15]([C:27]([OH:29])=O)=[N:16][C:17]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:18][N:19]=1.[CH3:30][O:31][C:32]1[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=1[NH2:34]>CN(C=O)C>[NH2:13][C:14]1[C:15]([C:27]([NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[O:31][CH3:30])=[O:29])=[N:16][C:17]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:18][N:19]=1
Reactant: Nc1ncc(Nc2ccccc2)nc1C(=O)O
Reactant: COc1ccccc1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)c1nc(Nc2ccccc2)cnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.7 %

Procedure:
CDI (92.98 mg, 0.5734 mmol) was added to a solution of 3-amino-6-anilino-pyrazine-2-carboxylic acid (110 mg, 0.4778 mmol) in DMF (1.5 mL) and the reaction stirred at ambient temperature for 1 hour. 2-Methoxyaniline (88.26 mg, 0.7167 mmol) was added and the reaction mixture left to stir at ambient temperature for 48 hours. The reaction mixture was purified directly by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as an orange solid (14 mg, 9% Yield). 1H NMR (400.0 MHz, DMSO) δ 3.84 (s, 3H), 6.90-7.10 (m, 6H), 7.29-7.33 (m, 2H), 7.53-7.55 (m, 2H), 8.13 (s, 1H), 8.41-8.43 (m, 1H), 9.18 (s, 1H) and 10.15 (s, 1H) ppm; MS (ES+) 336.07.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.O[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:43][CH:42]=1>C1COCC1>[N:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[O:32][CH2:40][C:41]1[CH:42]=[CH:43][C:44]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:46]=1
Reactant: COC(=O)c1ccc(CO)cc1
Reactant: Oc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
Triphenyl phosphine (614 mg) and a THF solution (1 mL) of diethyl azodicarboxylate (408 mg) were added in that order to a THF solution (20 mL) of 2-hydroxypyridine (149 mg) and methyl 4-hydroxymethylbenzenecarboxylate (260 mg), and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 2/3 to ethyl acetate alone) to obtain the entitled compound (85 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[C:11]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12]>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Product: Nc1nc(=O)n(C(=O)Oc2ccccc2)cc1F
Temperature: 65 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol (1.0 g, 7.74 mmol) in CH3CN (20 mL) was added BSA (2.84 mL, 11.61 mmol), and the mixture was heated to 65° C. for 1 h. The resulting solution was cooled to room temperature and to it was added phenyl chloroformate (2.4 mL, 19.35 mmol) causing a slight exotherm. The mixture was stirred at room temperature overnight. The suspension that formed was suction filtered, and the solid was washed with Et2O (3×10 mL). The solid was suspended in Et2O (10 mL) for 2 h, was collected via suction filtration and was air-dried overnight. Phenyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (0.90 g, 47%) was isolated as a white solid: mp 175-180° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.25 (br s, 2H), 8.45 (d, J=7.25 Hz, 1H), 7.49-7.43 (m, 2H), 7.35-7.28 (m, 3H); ESIMS m/z 250 ([M+H]+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][NH:11][C:12]1[CH:16]=[CH:15][NH:14][C:13]=1[C:17]([O:19]CC)=O.C(Cl)Cl.C([N:33]=[C:34]=[S:35])(=O)C1C=CC=CC=1>CO>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[CH2:10][N:11]1[C:12]2[CH:16]=[CH:15][NH:14][C:13]=2[C:17](=[O:19])[NH:33][C:34]1=[S:35]
Reactant: CCOC(=O)c1[nH]ccc1NCc1nc2ccccc2[nH]1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=S)n(Cc2nc3ccccc3[nH]2)c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 168.2 %

Procedure:
Ethyl 3-[(1H-benzimidazol-2-ylmethyl)amino]-1H-pyrrole-2-carboxylate (0.33 g, 1.16 mmol) was added to CH2Cl2 (3 mL) and methanol was added until clear solution was obtained. The solution was stirred at r.t. for 1 h. Benzoyl isothiocyanate (0.73 mL, 0.46 mmol) was added and after stirring at r.t. for 30 minutes the mixture was concentrated. The residue was dissolved in ammonia (7N in methanol, 7 mL) and the mixture was heated at 80° C. in a sealed steel container for 2 h. After cooling to r.t. the precipitated product was filtrated and washed through with methanol, diethyl ether and ethyl acetate, obtaining 0.23 g (66%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([NH2:14])=[CH:7][CH:6]=1)=[O:4].[O:15]=[CH:16][C:17]([Cl:20])([Cl:19])[Cl:18]>COCCOCCOC>[OH:15][CH:16]([NH:12][C:10](=[O:11])[C:9]1[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=1)[NH2:14])[C:17]([Cl:20])([Cl:19])[Cl:18]
Reactant: COC(=O)c1ccc(N)c(C(N)=O)c1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: COCCOCCOC
Product: COC(=O)c1ccc(N)c(C(=O)NC(O)C(Cl)(Cl)Cl)c1

Procedure:
5-Methoxycarbonylanthranilamide (1.0 g.) anhydrous chloral (5 ml.) and bis(2-methoxyethyl) ether (20 ml.) were heated together on a steam bath for 20 minutes, then evaporated to dryness under reduced pressure. The residue solidified on stirring with diethyl ether, and it was filtered off and purified by chromatography on silica gel (250 g.). The column was eluted with a mixture of ethyl formate and toluene (7:3 by volume), and 50 ml. fractions were collected. Fractions 10 to 13 were combined and evaporated to dryness, and the residue solidified on stirring with petroleum ether (b.p. 60°-80° C.) to give the required starting material, N-(1-hydroxy-2,2,2-trichloroethyl)-5-methoxycarbonylanthranilamide, m.p. 93° C. (with decomposition).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:5]=1[NH:6][C:7](=[O:10])[CH2:8][Cl:9])([O-:3])=[O:2].[CH3:18][O:19][CH2:20]Cl.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:9][CH2:8][C:7]([N:6]([CH2:18][O:19][CH3:20])[C:5]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])=[O:10]
Reactant: COCCl
Reactant: O=C(CCl)Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COCN(C(=O)CCl)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reaction time: 0.83 h
Yield: 80 %

Procedure:
To a 500 ml. stirred flask was added 3.0 g. (0.012 moles) of 2',6'-dinitro-2-chloroacetanilide, 2.5 ml. of chloromethyl methyl ether, 1.0 g. of phase transfer catalyst and 150 ml. of methylene chloride. Thereafter, 75 ml. saturated sodium carbonate solution was added in one portion and stirring continued for 50 minutes. At the end of this period, water was added to aid separation and the aqueous/organic mixture was allowed to stand overnight. The product, 2-chloro-2',6'-dinitro-N-(methoxymethyl)acetanilide, 2.9 g. m.p. 105.5°-108° C. was obtained in 80% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([S:11]([F:14])(=[O:13])=[O:12])=[CH2:10]>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]=[CH:9][S:11]([F:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: C=CS(=O)(=O)F
Reactant: Cc1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NC=CS(=O)(=O)F)cc1
Yield: 34.7 %

Procedure:
The reaction between 4-methylaniline (1.61 g, 15 mmol) and ethenesulfonyl fluoride (2.18 g, 19 mmol) was carried out in DMF (30 mL) at ambient temperature for 2.5 hours as described in Example 16. There was obtained a tan residue which was crystallized from ether/hexane to afford the title compound as a tan solid (1.12 g 34% yield), mp 61°-65° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:17]1([CH3:28])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[N:25]=[C:26]=[S:27]>CO>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:13][C:26]([NH:25][C:18]2[C:17]([CH3:28])=[CH:22][C:21]([CH3:23])=[CH:20][C:19]=2[CH3:24])=[S:27])[CH:14]=[CH:15][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N)c1
Solvent: CO
Product: Cc1cc(C)c(NC(=S)Nc2cccc(CO[Si](C)(C)C(C)(C)C)c2)c(C)c1

Procedure:
To 0.45 g (1.9 mmol) of 3-(tert-butyldimethylsilyloxymethyl)aniline in 3 mL of methanol was added 0.67 g (3.8 mmol) of mesitylisothiocyanate. The mixture was heated at reflux for 18 h. The mixture was concentrated and purified by flash chromatography eluting with a 16% ethyl acetate/hexanes mixture to give 0.56 (71%) of the title compound as a sticky white solid.