Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([CH2:11][OH:12])[CH2:9][CH2:10][C@@H:2]12.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[N:6]1[CH2:5][CH2:4][N:3]2[CH2:7][C@H:8]([CH2:11][OH:12])[CH2:9][CH2:10][C@H:2]2[CH2:1]1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Cis-(octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol (1 eq), 2-chloro-pyrimidine (1 eq.), and Na2CO3 (1 eq.) were dissolved in water. The mixture was stirred at around 95° C. for overnight. The solution was cooled to room temperature and extracted with methylene chloride. The combined organic layers was washed with brine, dried over Na2SO4, filtered and concentrated to give cis-(2-pyrimidin-2-yl-octahydro-pyrido[1,2-a]pyrazin-7-yl)-methanol as a white solid. This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([OH:17])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[Br:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]Br>O.CCOCC.C(#N)C>[CH3:1][O:2][C:3]([C@@:5]1([CH3:19])[CH2:10][CH2:9][C:8]2[C:11]([CH3:18])=[C:12]([O:17][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][Br:44])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1)=[O:4]
Reactant: BrCCCCCBr
Reactant: COC(=O)[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: COC(=O)[C@@]1(C)CCc2c(C)c(OCCCCCBr)c(C)c(C)c2O1
Yield: 95.5 %

Procedure:
A mixture of 6.5 g (24.6 mmoles) of (R)-(+)-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester, 10.37 g (75.1 mmoles) of anhydrous potassium carbonate, 1.12 g of 18-crown-6, 39.3 ml (0.2 mole) of 1,5-dibromopentane, and 150 ml of acetonitrile was stirred and refluxed for 21 hours. After being cooled, the mixture was treated with ether and water. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (68 g) was purified first by column chromatography on silica gel (400 g; eluting with 49:1 toluene-ethyl acetate) and then by preparative HPLC on silica gel using 9:1 hexane-ethyl acetate as the mobile phase. There was obtained 9.71 g (95.6%) of (R)-(+)-6-[(5-bromopentyl)oxy]-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a solid. Recrystallization from ethanol gave a colorless solid mp 64°- 65.5° C., [α]D25 +36.37° (c2, CHCl3).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([OH:21])[CH:20]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:21][C:19]2[CH:20]=[C:15]([C:13](=[O:14])[CH3:12])[CH:16]=[CH:17][CH:18]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Reactant: CC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 3-hydroxyacetophenone (5.5 g, 42.2 mmol), and K2CO3 (11.7 g, 84.6 mmol) in DMF (50 mL). The mixture was heated at 80° C. for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The crude product was purified by flash chromatography eluting with (hexanes/ethyl acetate 70:30) to give the title compound (8.6 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)=O.[CH3:18][C:19](=O)[CH2:20][C:21](=[O:23])[CH3:22]>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:18][C:19]1[N:1]=[C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]2=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:20]=1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)CC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1cccs1)CCCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)c1c(C)nc2sc3c(c2c1-c1cccs1)CCCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-thiophen-2-yl-methanone (the preparation of which is described in example 6) in 1.5 ml acetic acid was added 0.020 ml (0.21 mmol) of pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 46 mg (74%) 1-(2-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a yellow oil. ES-MS m/e (%): 328 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:16])[C:5]2[CH:6]=[CH:7][C:8](=[O:15])[N:9]([CH2:12][CH:13]=C)[C:10]=2[CH:11]=1.O.I([O-])(=O)(=O)=[O:19].[Na+]>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:19])=[N+:4]([O-:16])[CH:3]=1
Reactant: C=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=CCn1c(=O)ccc2c1cc(F)c[n+]2[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)-1,5-naphthyridin-2(1H)-one 5-oxide (340 mg, 1.544 mmol) was stirred in 1,4-dioxane (16 mL) and water (8 mL) was added, followed by sodium periodate (990 mg, 2.3 eq.) and osmium tetroxide (1 mL of 4% aqueous solution). The mixture was stirred at room temperature for 3 hours. The solvents were evaporated under reduced pressure (water bath temperature 30° C.) to a volume of ca. 10 mL, and the residue was extracted with 20% methanol in DCM (v:v, 3×50 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give (7-fluoro-5-oxido-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde largely as its methyl hemiacetal) as a tan foam (327 mg). LCMS showed major peaks for the aldehyde hydrate (32%) and the methyl hemiacetal (64%).
Reaction SMILES: [C:1]([N:4]1[CH:10]2[CH:8]([CH:9]2[CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:6](=[O:28])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:44](OCC)(=[O:50])[C:45](OCC)=[O:46].Cl>CN(C=O)C>[CH2:13]([O:12][CH2:11][CH:9]1[CH:10]2[CH:8]1[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:6](=[O:28])[C:5]1[N:4]2[C:1](=[O:3])[CH:2]=[C:44]([OH:50])[C:45]=1[OH:46])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)C2C(COCc3ccccc3)C21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1c2c(O)c(O)cc(=O)n2C2C(COCc3ccccc3)C2N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 5-acetyl-2-(4-fluorobenzyl)-7-[(benzyloxy)-methyl]-2,5-diazabicyclo[4.1.0]heptane-3-one (700 mg, 1.83 mmol) in DMF (10 mL) under nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1.0 M, 2.0 mL, 2.0 mmol) was added. After 30 min, diethyl oxalate (401 mg, 2.74 mmol) in DMF (2 mL) was added. After stirring for 1 h at room temperature, the resultant mixture was treated with additional lithium bis(trimethylsilyl)amide (1.0 M, 7.1 mL, 7.1 mmol), and stirred at room temperature overnight. The reaction mixture was treated with 1 N HCl, concentrated under vacuum. The residue was partitioned between brine and chloroform. The aqueous layer was extracted with chloroform twice. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.CS(O[CH2:17][CH2:18][CH2:19][O:20][CH3:21])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:6]=2[CH:11]=1
Reactant: COCCCOS(C)(=O)=O
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCn1c(=O)oc2ccc(Br)cc21
Temperature: 70 °C
Yield: 102 %

Procedure:
A mixture of 5-bromobenzo[d]oxazol-2(3H)-one (1.1 g), 3-methoxypropyl methanesulfonate (1.297 g) and potassium carbonate (2.131 g) in acetonitrile (25 mL) was heated at 70° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried (MgSO4), evaporated and purified by flash chromatography (silica, isohexane-acetone (5:1) as eluent) to give the sub-titled compound (1.50 g) as an oil.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:17][C@H:18]1[CH2:35][C@@H:34]([CH3:36])[C@@:33]2([CH2:37][OH:38])[C@@H:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:32]2[CH2:31][CH2:30][C@@:28]2([CH3:29])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[O:39]C(=O)C)[CH2:19]1)(=[O:16])[CH3:15]>CC(C)=O>[C:14]([OH:17])(=[O:16])[CH3:15].[C:14]([OH:17])(=[O:16])[CH3:15].[OH:17][C@H:18]1[CH2:35][C@@H:34]([CH3:36])[C@@:33]2([CH:37]=[O:38])[C@@H:20]([CH2:21][CH2:22][C@@H:23]3[C@@H:32]2[CH2:31][CH2:30][C@@:28]2([CH3:29])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[OH:39])[CH2:19]1
Reactant: CC(=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]3[C@@]2(CO)[C@H](C)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC(=O)O
Product: C[C@@H]1C[C@H](O)C[C@@H]2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21C=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
One equivalent of Jones reagent is added dropwise to a stirred solution of 1β-methyl-5α-androstane-3β,17β,19-triol 3,17-diacetate in acetone chilled to 0° C. After 15 minutes at 0° C., the acetone layer is poured onto ice water. The solid which forms is filtered and crystallized from an ether-hexane solution to yield 3β,17β-dihydroxy-1β-methyl-5α-androstan-19-one diacetate. This material is dissolved in aqueous methanol containing sodium carbonate and the solution heated at its reflux temperature for about 4 hours. The cooled solution is poured onto water and filtered. The solid which forms is collected and is crystallized from an ether-hexane solution to yield 3β,17β-dihydroxy-1β-methyl-5α-androstan-19-one.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#N)[CH3:3].O=[Al]O[Al]=O.[C:12]1([CH3:23])[CH:17]=[CH:16][C:15]([S:18]([O:21]C)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(#N)C>[C:12]1([CH3:23])[CH:13]=[CH:14][C:15]([S:18]([O-:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[C:4](#[N:2])[CH3:5].[CH3:1][NH+:2]([CH3:4])[CH3:3]
Reactant: CN(C)CC#N
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=[Al]O[Al]=O
Solvent: CC#N
Product: C[NH+](C)C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 156.4 %

Procedure:
Dimethylamino acetonitrile (4.2 g, 0.05 mole) was dissolved in dry acetonitrile (50 ml) in a 100 ml RB flask provided with condenser, calcium chloride drying tube, and anti-bumping granules. Methyl p-toluene sulphonate (9.3 g, 0.05 mole) was added and the solution refluxed for 5 hours. The flask was cooled in ice, and the white solid crystalline solid filtered off, washed with ice-cold dry acetonitrile and then vacuum-dried to give 10.65 g of product, yield 78.8%: 'H NMR (σ, D2O) 2.4 (s, 3H, CH3 -Ar), 3.4 (s, 9H, (CH3)3N+), 7.4+7.7 (dd, 4H, ArH) ppm.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)(=O)C.C1(C)C=CC=CC=1>C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:21]2[CH:20]=[CH:19][C:18]([OH:17])=[CH:23][CH:22]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)Oc1ccc(I)cc1
Reactant: C#Cc1ccc(CCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(C#Cc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-Pentylphenylacetylene (10.5 g, 61.4 mmol), 4-acetoxyphenyl iodide (16.1 g, 61.4 mmol), a catalytic amount of Pd(PPh3)2Cl2 and a catalytic amount of copper iodide were stirred in diisopropylamine (100 ml) at 70° C. After 5 minutes, a precipitate was seen and the mixture became unstirrable, toluene (100 ml) was added. The mixture was stirred at room temperature for 24 hours and then evaporated to dryness on a rotary evaporator. The residue was redissolved in aqueous potassium hydroxide ethanolic solution and stirred at 70° C. overnight. The mixture was evaporated to dryness, then partitioned between ethyl acetate and water, the organic phase was removed, dried and evaporated. The residue was purified by flash column chromatography using DCM as eluant. A pink coloured solid was left after evaporation of the appropriate fractions. Yield=10.4 g, 64%. 1H-NMR and IR spectroscopy gave the expected signals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1.[CH3:22][N:23]=[C:24]=[O:25]>C(Cl)(Cl)Cl>[CH3:22][NH:23][C:24]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[C:11]([F:21])[CH:10]=2)[CH3:8])[N:6]=1)=[O:25]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1csc(N)n1
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)Nc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 83.6 %

Procedure:
To 2-amino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (500 mg, 1.68 mmol) in chloroform (20 ml) was added methylisocyanate (0.10 mg, 1.75 mmol) in chloroform (10 ml) under cooling with ice. After the mixture was stirred, methylisocyanate (0.15 mmol, 2.63 mmol) was added to the mixture, and then the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure to a residue, which was crystallized to afford N-methyl-N'-(4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazol-2-yl)urea (0.499 g, 84% yield) as crystalline material: mp 208.5°-209.0° C.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([O-:9])=[O:8].[ClH:19].[C:20]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29]([CH2:33][C:34](=[O:36])[NH2:35])=[C:28](O)[CH:27]=[CH:26]2)(=[NH:22])[NH2:21].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[ClH:19].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:20](=[NH:21])[NH2:22])[CH:24]=3)[C:29]=2[CH2:33][C:34](=[O:36])[NH2:35])=[O:15])=[CH:17][CH:18]=1)([O-:9])=[O:8]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc([N+](=O)[O-])cc3)ccc2c1
Reaction time: 2 h
Yield: 29.4 %

Procedure:
30 Milliliters of anhydrous pyridine and 10 ml of DMF were added to 1.8 g of 4-nitrobenzoic acid, 3.0 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.7 g of DCC and 130.9 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. Then, the precipitate was collected by filtration and washed with a small amount of DMF. To this collected precipitate was added 100 ml of DMF, to dissolve the precipitate with heating, followed by stirring for 2 hours under cooling with ice. Then, insoluble matter was filtered off and the filtrate was concentrated to 20 ml under reduced pressure. The residue was added dropwise to 400 ml of acetone, followed by stirring for 24 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using chloroformmethanol-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. The residue was suspended with addition of 20 ml of methanol and 0.6 ml of concentrated hydrochloric acid, and the suspension was added dropwise to a mixed liquid of 200 ml of ether and 20 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.35 g of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-nitrobenzoate.hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH:37]([C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1)[NH2:38]>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:38][NH:37][C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:47][CH:48]=1)=[O:8])#[N:2]
Reactant: COC(=O)c1ccc(NN)cc1
Reactant: N#Cc1cccc(C(=O)O)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(NNC(=O)c2cccc(C#N)c2)cc1
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
At 0° C., to a suspension of 3-cyanobenzoic acid (0.62 g, 4.2 mmol) in dichloromethane (15 mL) is added THE dropwise until the system became homogenous, which is followed by the addition of 1-hydroxybenzotriazole (0.57 g, 4.2 mmol) and dicyclohexylcarbodiimide (0.87 g, 4.2 mmol). The mixture is brought to room temperature slowly and stirred for 0.5 h. To the mixture, methyl 4-hydrazinobenzoate (0.63 g, 3.8 mmol) is added and the mixture is stirred for 2 hr. The precipitate is then removed by filtration and washed with dichloromethane. The filtrate is washed with water and brine, dried over anhydrous Na2SO4, which is discarded later. The crude product obtained after the removal of the solvent is separated by column chromatography (silica gel, 1:19 ethyl acetate-dichloromethane) to provide the intermediate, methyl 4-[2-(3-cyanobenzoyl)hydrazino]benzoate (0.68 g, 61%). MS (ES+) m/z: 296.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)=O.[N+]([O-])(O)=O.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH:30][C:31]([NH2:33])=[NH:32]>>[CH3:14][O:13][C:11]1[CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:33]=[C:31]([NH:30][C:22]3[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=[CH:26][C:21]=3[CH3:20])[N:32]=2)[CH:8]=[N:9][CH:10]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Reactant: COc1cncc(C(=O)C=CN(C)C)c1
Solvent: O=[N+]([O-])O
Product: COc1cncc(-c2ccnc(Nc3cc([N+](=O)[O-])ccc3C)n2)c1

Procedure:
Condensation of 12 with N-(2-methyl-5-nitro-phenyl)-guanidine nitrate 2 using a similar procedure for the preparation of 4 affords 4-(5-methoxypyridin-3-yl)-N-(2-methyl-5-nitrophenyl)pyrimidin-2-amine 13. 1H NMR (400 MHz, d6-DMSO) δ 9.23 (s, 1H), 8.93 (d, J=1.2 Hz, 1H), 8.80 (d, J=2.0 Hz, 1H), 8.63 (d, J=5.2 Hz, 1H), 8.44 (d, J=2.8 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=2.0, 8.4 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 3.90 (s, 3H), 2.44 (s, 3H). MS (m/z) (M+1)+: 338.1
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:13])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH:14]1CCCC[CH2:15]1.N1C=NC=NC=1>CO>[Br:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:15][NH:14][C:4]2=[O:5]
Reactant: C1CCNCC1
Reactant: COc1cc(N)c(C(=O)O)cc1Br
Agent: c1ncncn1
Solvent: CO
Product: COc1cc2nc[nH]c(=O)c2cc1Br
Temperature: 25 °C
Yield: 63 %

Procedure:
2-Amino-5-bromo-4-methoxybenzoic acid (1.56 g, 6.34 mmol) is dissolved in methanol (15 ml), treated with piperidine (0.063 ml, 0.63 mmol) and 1,3,5-triazine (772 mg, 9.5 mmol) and refluxed for one hour. After cooling to room temperature, the resulting crystals are filtered off with suction and washed with methanol. The desired product is obtained in 63% yield (1.01 g).
Reaction SMILES: [CH3:1][N:2]([C:9](=[O:18])[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+]>CO.O>[CH3:1][N:2]([C:9](=[O:18])[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)CN(C)C(=O)C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(CC(=O)O)C(=O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a 0° C. solution of ethyl 2-(N-methyl-3-phenylprop-2-ynoylamino)acetate (prepared according to the procedure described for Intermediate A, 124.4 g, 0.507 mol) in MeOH (750 mL) was added a solution of NaOH (30.4 g, 0.760 mol, 1.5 equiv) in water (1000 mL). The resulting red reaction mixture was stirred for 20 min, then allowed to warm to room temperature and stirred for 2 h. The reaction was washed with CH2Cl2 (3×500 mL). The aqueous layer was cooled in an ice bath and acidified to pH 3 using conc. HCl. A light orange oil formed, which was extracted into EtOAc (4×500 mL). The combined EtOAc layers were washed with water (3×200 mL) and a saturated NaCl solution (2×300 mL), dried (Na2SO4) and concentrated under reduced pressure to give 2-(N-methyl-3-phenylprop-2-ynoylamino)acetic acid (102.5 g, 93%) as an orange solid: TLC (1% AcOH/5% MeOH/CH2Cl2) Rf 0.20; 1H NMR (CDCl3) δ 3.09 (s, 1.1H, N—CH3), 3.36 (s, 1.9H, N—CH3), 4.27 (s, 1.2H, N—CH3), 4.45 (s, 0.8H, N—CH3), 7.30-7.56 (m, 5H), 9.58 (br s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][N:19]=2)=[O:17])[CH2:12][CH2:11]1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>CO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][N:19]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccc(Br)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ccccc2)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a stirred mixture of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-bromopyridin-2-yl)methanone (39 mg, 0.10 mmol) and phenylboronic acid (20.1 mg, 0.17 mmol) in a mixture of MeOH (0.5 mL) and 1,4-dioxane (1.5 mL) is added 2M aqueous NaHCO3 (0.3 mL). The mixture is degassed with N2. 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (5 mol %) is added and the mixture is heated at 100° C. under microwave irradiation for 30 mins. The mixture is filtered through a pad of celite and the filtrate is concentrated under reduced pressure. Purification by column chromatography (Isolute column, eluent DCM, 5% MeOH) affords 30.6 mg of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-phenylpyridin-2-yl)methanone.