Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:9])[N:3]=1.[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([CH3:9])[C:5]([NH:8][C:17](=[N:18][C:19]#[N:20])[O:16][C:13]2[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1nc(N)ccc1N
Solvent: COCCOC
Product: Cc1nc(N)ccc1NC(=NC#N)Oc1ccccc1
Yield: 41.2 %

Procedure:
A stirred mixture of the product from Step 1 (4.34 g, 0.0353 mol), diphenylcyanocarbonimidate (8.4 g, 0.0353 mol) and ethylene glycol dimethyl ether (40 ml) was kept under nitrogen at ambient temperature (25° C.) for 18 hours. The mixture was concentrated and the residue was purified by silica gel chromatography and crystallization from MeOH-EtOAc-hexane to give 3.89 g of the titled product, mp 189°-190° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH2:19])=[S:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:16][C:17]2[S:18][CH:21]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=2)[CH:8]=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(N)=S)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)C(=O)CBr
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)n1
Yield: 51.6 %

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenylthiourea (2.60 g) and 2.01 g of ethyl bromopyruvate were dissolved in 100 ml of ethanol, and the solution was heated under reflux for 3 hours. After addition of water, the reaction mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, then dried over magnesium sulfate, and concentrated. Purification of the crude product by silica gel column chromatography (chloroform-ethyl acetate=15:1) gave 1.80 g of the desired compound.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].Cl.N([O-])=O.[Na+].[S-:19][S-].[Na+].[Na+]>O>[SH:19][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:13])[CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [S-][S-]
Reactant: CC(=O)c1cccc(N)c1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cccc(S)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
10.2 g of 2-amino-6-acetylbenzoic acid was converted into a diazonium salt with a mixture of 14.2 ml of concentrated hydrochloric acid, 40 ml of water and 4.3 g of sodium nitrite, and the diazonium salt was gradually added dropwise at a temperature of 0 to 5° C. to a sodium disulfide aqueous solution (prepared from 14.3 g of sodium sulfide.9H2O, 1.9 g of sulfur, 4.6 g of sodium hydroxide and 30 ml of water). After adding dropwise, the reaction liquor was stirred for 2 hours at room temperature to complete the reaction. The reaction liquor was poured into a large amount of water, and after adding concentrated hydrochloric acid thereto, the product was extracted with ethyl acetate. To the ethyl acetate layer, was added sodium hydrogencarbonate aqueous solution, and the content soluble in sodium hydrogencarbonate was extracted. To the resultant aqueous solution, was added 14.8 g of sodium pyrosulfate, and the mixture was refluxed for 30 minutes to complete the reaction. To the reaction liquor, was added concentrated hydrochloric acid, and the product was extracted with ethyl acetate. The extracted liquor was dried, and the solvent was distilled off under reduced pressure to obtain 10.1 g of 2-mercapto-6-acetylbenzoic acid at a yield of 90%.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3](Br)=[O:4].[C:9]([O:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>ClCCl>[Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])=[CH:22][CH:21]=1)=[O:4]
Reactant: O=C(Br)C(Br)CCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)C(Br)CCBr)cc1
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
To the derivative 2,4- dibromobutyryl bromide (3.1 g) in dry dichloromethane (60 ml) pyridine (3.2 ml) was added, the mixture was kept at 0° C. under a nitrogen atmosphere for 10 minutes and then the N-t-butoxy carbonyl-1,4 phenylene diamine (2.08 g) was dropped. After 1 hour the mixture was poured into a saturated solution of NH4Cl (200 ml) extracted with EA (3×150 ml) and the organic phase washed with brine (200 ml), dried and concentrated in vacuum, the crude was purified by flash chromatography (eluting with CH/EA 80:20) to give of the title compound as a yellow foam (3.5 g ). T.I.c. CH/EA 8:2, Rf=0.53.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[CH:19][CH:20]=2)[C:11](=[O:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCO
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Yield: 66.6 %

Procedure:
4-Benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one (150 mg, 0.511 mmol), 2-(dimethylamino)ethanol (0.057 mL, 0.562 mmol), triphenylphosphine (269 mg, 1.02 mmols) and diethyl azodicarboxylate (0.163 mL, 1.02 mmols) were stirred overnight in THF (4 mL). Concentrating the reaction liquid under reduced pressure, the resulting residue was purified on silica gel column chromatography (C-300, methanol: chloroform=1:20-1:10) to provide the title compound (124 mg, 60%).
Reaction SMILES: [N+]([O-])(O)=O.[C:5]1([NH:11][C:12]([NH2:14])=[NH:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][O:16][CH2:17][C:18]([CH2:20][C:21](=O)[CH3:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:11]([C:12]1[N:14]=[C:18]([CH2:17][O:16][CH3:15])[CH:20]=[C:21]([CH3:22])[N:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COCC(=O)CC(C)=O
Reactant: N=C(N)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: COCc1cc(C)nc(Nc2ccccc2)n1
Temperature: 25 °C
Yield: 67.2 %

Procedure:
A mixture of 4.5 g of phenylguanidine nitrate, 3.3 g of methoxyacetylacetone and 12 g of anhydrous sodium carbonate was heated with stirring and allowed to react at 150° C. for 2 hours. After cooling to room temperature, water was added to the reaction mixture, which was then extracted with 150 ml of toluene. The toluene layer was washed with water, dried over Glauber's salt and concentrated by evaporation under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3.5 g (yield: 68%) of 2-anilino-4-methoxymethyl-6-methylpyrimidine.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].C(N(CC)CC)C.O=[S:22]1[CH2:27][CH2:26][CH2:25][N:24]2[C:28](=[O:42])[N:29]([CH2:39][CH2:40][CH3:41])[C:30](=[O:38])[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:23]12>C(Cl)Cl>[OH:4][CH:27]1[S:22][C:23]2=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:30](=[O:38])[N:29]([CH2:39][CH2:40][CH3:41])[C:28](=[O:42])[N:24]2[CH2:25][CH2:26]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCC(O)S2
Temperature: 40 °C
Reaction time: 60 h
Yield: 77.5 %

Procedure:
Trifluoroacetic anhydride (3.78 g) and triethylamine (1.82 g) were added to a solution of 1-oxo-9-phenyl-7-propyl-3,4-dihydro-2H,6H-pyrimido[6,1-b][1,3]thiazine-6,8(7H)-dione (4 g) in methylene chloride (60 ml) and the mixture was stirred at 40° C. for 60 hours. The reaction solution was evaporated to dryness, and the residue was dissolved in methylene chloride-H2O. Then, the organic layer was washed with a saturated aqueous sodium bicarbonate. After drying, the organic solution was concentrated, and the resulting residue was purified by column chromatography on silica gel. The resulting crude crystals were recrystalized from methylene chloride-isopropyl ether to give colorless needles (3.1 g, 78%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)=[O:19])[C:13]=1[OH:34]>O1CCCC1>[CH:1]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)=[O:19])[C:13]=1[OH:34])=[O:3]
Reactant: Nc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Yield: 78 %

Procedure:
There is heated at reflux 61.2 mg of acetic anhydride and 27.6 mg of formic acid for 4 hours and 46 mg of 4-amino-3-hydroxy-N-para-phenoxyphenylpicolin-amide of Example 2 is added, dissolved in 5 ml of tetrahydrofuran. After 8 hours at reflux, the reaction mixture is concentrated and purified by chromatography to give 39 mg of a yellow solid MP 208° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](Cl)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.CN1CCCC1=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:23][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)cc1
Reactant: NC1CCCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc(-c2nc3c(c(NC4CCCC4)n2)CCC3)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.265 g of 2-(4-chlorophenyl)-4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, 0.4 g of cyclopentylamine and 1 ml of N-methylpyrrolidone were heated to 130° C. in an oil bath. After 5 hours, the mixture was diluted with 20 ml of water and stirred at room temperature. The precipitated product was filtered off with suction, washed with water and dried in vacuo at 40° C.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](N2C=CN=C2)=[S:20])=[N:16][CH:17]=1>>[C:1]1([C@H:7]2[CH2:9][C@H:8]2[NH:10][C:19]([NH:18][C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][N:16]=2)=[S:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(Nc1ccc(Cl)cn1)n1ccnc1
Reactant: N[C@@H]1C[C@@H]1c1ccccc1
Product: S=C(Nc1ccc(Cl)cn1)N[C@@H]1C[C@@H]1c1ccccc1

Procedure:
(-)-N-cis-2-phenylcyclopropylamine (0.23 g, 1.7 mmol) from Example 423 was condensed with 1-(5-chloropyrid-2-yl-thiocarbamoyl)-imidazole (0.4 g, 1.7 mmol) according to the procedure of Example 372 to yield the titled product as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccc(Cl)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.35 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 17.5 g. of p-chlorobenzoyl chloride are reacted. The benzene is evaporated and the dark purple residue is dissolved in 200 ml. of chloroform and washed successively with 5% sodium carbonate, 0.5N Hydrochloric acid and then with water and dried over sodium sulfate giving a dark purple oil. The oil is extracted with ether giving the product as grey crystals, mp 98°-100° C.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24](=[O:26])[CH3:25]>>[CH3:22][O:23][C:24](=[O:26])[CH2:25][C:2]1[CH:21]=[CH:20][CH:5]=[C:4]([C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:19])=[C:7]([C:9](=[O:10])[C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=4[Cl:18])[O:8][C:4]=3[CH:3]=2)[CH:3]=1
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Reactant: COC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1

Procedure:
{3-[2-(2,4-Dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-phenyl}-acetic acid methyl ester was prepared via a Suzuki coupling of (6-Bromo-3-methyl-benzofuran-2-yl)(2,4-dichloro-phenyl)-methanone and 3-Bromo-phenyl)-acetic acid methyl ester as described in method 1 step 5. MS ES (MH+) 453.1, RT=4.27 min).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=O.[NH2:20][C:21]1[S:25][CH:24]=[C:23]([C:26]#[N:27])[C:22]=1[N:28]1[CH:32]=[CH:31][N:30]=[N:29]1>>[C:26]([C:23]1[C:22]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)=[C:21]([NH:20][C:17](=[O:19])[CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]2=[O:1])[S:25][CH:24]=1)#[N:27]
Reactant: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reactant: N#Cc1csc(N)c1-n1ccnn1
Product: N#Cc1csc(NC(=O)Cn2c(=O)ccc3cc(C(F)(F)F)ccc32)c1-n1ccnn1

Procedure:
The title compound was prepared from 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (0.072 g, 0.27 mmol) and 5-amino-4-(1H-1,2,3-triazol-1-yl)thiophene-3-carbonitrile (0.025 g, 0.13 mmol) according to protocol A. The crude product was purified by prep HPLC. LCMS retention time (min)=5.505, method [7], MS (ESI) 445.1 (M+H). 1H NMR (CDCl3) δ 11.17 (s, 1H), 8.41 (s, 1H), 7.91-7.87 (m, 3H), 7.79 (d, J=9.0 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]=[O:13].[CH2:14]([NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([O:34][CH3:35])[CH2:31][O:32][CH3:33])=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(#N)C>[CH3:35][O:34][CH:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:21]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:12]([NH:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])=[O:13])=[CH:28][CH:27]=1)[CH2:31][O:32][CH3:33]
Reactant: CCCCCCCNCc1ccc(OC(COC)OC)cc1
Reactant: COc1ccc(N=C=O)c(OC)c1
Solvent: CC#N
Product: CCCCCCCN(Cc1ccc(OC(COC)OC)cc1)C(=O)Nc1ccc(OC)cc1OC
Reaction time: 48 h
Yield: 85.1 %

Procedure:
2,4-Dimethoxyphenyl isocyanate (Aldrich, 5.6 g) was added in one portion to a stirred solution of the product from step (c) (10.3 g) in acetonitrile (50 ml). The mixture was stood at room temperature for 2 days and then evaporated in vacuo to give a mobile pale tan oil which was flash chromatographed through a silica column using cyclohexane/ethyl acetate (1:1) as eluant to give the desired product as a colourless oil (13.0 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:11])[C:4]([O:9][CH3:10])=[CH:5][C:6](=[O:8])[CH:7]=1.[Si](O[N:20]=[CH:21][CH:22]=[CH:23][CH3:24])(C(C)(C)C)(C)C>ClC1C=CC=CC=1>[CH3:10][O:9][C:4]1[C:3](=[O:11])[C:2]2[N:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:7]=2[C:6](=[O:8])[CH:5]=1
Reactant: CC=CC=NO[Si](C)(C)C(C)(C)C
Reactant: COC1=CC(=O)C=C(Br)C1=O
Solvent: Clc1ccccc1
Product: COC1=CC(=O)c2c(C)ccnc2C1=O
Yield: 46.9 %

Procedure:
In a 50 mL round bottom flask 2-bromo-6-methoxy-1,4-benzoquinone (282 mg, 1.3 mmol) was dissolved in dry chlorobenzene (28 mL) along with 1-(tert-butyldimethylsilyloxy)-1-aza-1,3-pentadiene (130 mg, 0.65 mmol). The solution was stirred and heated to reflux for 4 days under N2. The dark reaction was allowed to cool and was added to a silica gel column (2.5×9 cm). The column was eluted with EtOAc/hexane (5:1) then EtOAc and finally ethanol. The solvent was removed, benzene was added, and the resulting mixture was heated and filtered to remove insoluble impurities. Evaporation of the filtrate gave 62 mg, 47% of the crude product. 1H NMR (CDCl3) δ2.76 (s, 3H), 3.93 (s, 3H), 6.20 (s, 1H), 7.52 (d, J=8 Hz, 8.30 (d, J=8 Hz, 1H).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][CH:11]=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:20]C1C2C(O2)CN(C(OCC)=O)C1>>[Si:1]([O:8][CH:9]1[CH:10]2[CH:11]([O:20]2)[CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)N1CC=CC(O[Si](C)(C)C(C)(C)C)C1
Reactant: CCOC(=O)N1CC(O)C2OC2C1
Product: CCOC(=O)N1CC2OC2C(O[Si](C)(C)C(C)(C)C)C1

Procedure:
Compound 239F was prepared from 239D in a same reaction as Compound 239E as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:15][CH:16]=O>CO>[NH2:12][C:10]1[N:11]2[CH:15]=[CH:16][N:1]=[C:2]2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][C:9]=1[Cl:13]
Reactant: COC(=O)c1cc(Cl)c(N)nc1N
Reactant: O=CCCl
Solvent: CO
Product: COC(=O)c1cc(Cl)c(N)n2ccnc12
Reaction time: 21 h
Yield: 67.9 %

Procedure:
A mixture of methyl 2,6-diamino-5-chloronicotinate (Example 1, METHOD B, Step 1, 2.0 g, 9.92 mmol) and chloroacetaldehyde (1.2 mL, 10.91 mmol) in methanol (100 mL) was refluxed for 135 min. A further chloroacetaldehyde (1.2 mL, 10.91 mmol) was added and refluxing continued over 21 hours. The solvent was evaporated and the resulting solid co-evaporated with methanol (75 mL×2) prior to drying under vacuum, giving 2.62 g of crude material. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% aqueous ammonia (96.5:3.5:0.5 to 93:7:1) to give 1.52 g (68%) of the title compound as an off white powder.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:11][CH:12]=1)[CH3:6]>O.C(O)(=O)C>[CH2:5]([C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](=[O:22])[C:16](=[N:1][OH:3])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:10]=[CH:11][CH:12]=1)[CH3:6]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)CCc1cccc(CC)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(CC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of sodium nitrite (6.3 g) in water (10 ml) was added to a stirred solution of the product from step (iii) (20.6 g) in acetic acid (30 ml) at <30° C. The reaction mixture was stirred at room temperature for 18 hours. Water (150 ml) was added and the mixture was stirred for 2 hours and extracted with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure.
Reaction SMILES: [C:1]([NH:3][C:4]([NH2:6])=[NH:5])#[N:2].[CH3:7][C:8](=O)[CH2:9][C:10](=O)[CH3:11].Cl>O>[C:1]([NH:3][C:4]1[N:6]=[C:10]([CH3:11])[CH:9]=[C:8]([CH3:7])[N:5]=1)#[N:2]
Reactant: CC(=O)CC(C)=O
Reactant: N#CNC(=N)N
Agent: Cl
Solvent: O
Product: Cc1cc(C)nc(NC#N)n1
Temperature: 120 °C
Yield: 69.9 %

Procedure:
A mixture of 42 g (0.5 mol) of cyanoguanidine ("dicyanodiamide") and 50 g (0.5 mol) of pentane-2,4-dione ("acetylacetone") is heated to 120° C. for 15 hours. Thereafter, after the reaction mixture has been cooled, 500 ml of water are added and the solution is acidified with hydrochloric acid at 0° C. to 10° C. The product obtained in crystalline form in this procedure is isolated by being filtered off under suction. 51.8 g (70% of theory) of 2-cyanoamino-4,6-dimethyl-pyrimidine of melting point 205° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:20][CH:22]3[CH2:23][O:24]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(-c2cc[nH]n2)cc1Cl
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccn(CC3CO3)n2)cc1Cl
Yield: 81.7 %

Procedure:
A stirred solution of 3-(3,4-dichlorophenyl)pyrazole (300 mg, 1.4 mmol) in DMF (5 mL) was treated with cesium carbonate (550 mg, 1.69 mmol) and epichlorohydrin (1.1 mL, 14.0 mmol) at room temperature for 18 h. The crude reaction mixture was then partitioned between EtOAc (50 mL) and water (35 mL). The aqueous phase was further extracted (2×50 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to yield crude product. Purification by column chromatography (silica, 25% EtOAc/hexanes) afforded 308 mg (82%) of the title compound. 1NMR (400 MHz, CDCl3): 7.83 (d, J=2 Hz, 1H), 7.54 (dd, J=2, 8 Hz, 1H), 7.44 (d, J=2 Hz, 1H), 7.38 (d, J=8 Hz, 1H), 6.48 (d, J=2 Hz, 1H), 4.45 (dd, J=3, 9.7 Hz, 1H), 4.12 (dd, J=6, 15 Hz, 1H), 3.31 (m, 1H), 2.81 (dd, J=4.0, 4.6 Hz, 1H), 2.47 (dd, J=2.6, 4.7 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].Cl.[OH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16](O)=[O:17].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[OH:14][C@@H:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([NH:1][C@@H:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:17]
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: COC(=O)[C@@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)[C@@H](O)CC(C)C)c1ccccc1

Procedure:
To a cooled (0° C.) solution of methyl (2S)-amino(phenyl)acetate (3.06 g), (2S)-2-hydroxy-4-methylpentanoic acid hydrochloride, NMM (1.85 ml), and HOBt (6.15 g) in dichloromethane (50 ml) was added EDAC-HCl (5.81 g). Additional NMM (2.31 ml) was then added. The mixture was stirred for 2h at 0° C., then overnight at RT. The reaction was concentrated and the residue was taken up in Ethyl acetate washed with 0.1N hydrochloric acid, saturated sodium bicarbonate, brine, dried, filtered and evaporated to afford the title compound (4.20 g). 1H NMR (300 MHz, CDCl3) δ 0.92-0.95 (m, 6H), 1.47-1.67 (m, 2H), 1.76-2.04 (m, 1H), 2.63 (bs, 1H), 3.74 (s, 3H), 4.21 (d, 1H, J=9 Hz), 5.58 (d, 1H, J=8 Hz), 7.26-7.42 (m, 5H). MS APCI, m/z=280 (M+1). LC/MS: 1.95 min.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:26])[CH2:12][C:13](=[O:25])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=2)=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:27][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:26])[CH2:12][C:13](=[O:25])[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=2)=[CH:5][CH:4]=1
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(N(C)C)cc2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)CC(=O)CCc2ccc(N(C)C)cc2)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.8 %

Procedure:
To a solution of (1E,6E)-1-(4-dimethylaminophenyl)-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (15 mg, 41 μmol, synthesized in Example 9) in 3.0 mL of ethyl acetate was added palladium 5% on carbon (30 mg) under nitrogen. After the vessel was purged with hydrogen, the reaction mixture was stirred under 1 atm of hydrogen at room temperature for 1.5 h. After the vessel was purged with nitrogen, the reaction mixture was filtered to remove palladium 5% on carbon. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 65/35) to obtain the title compound as a gum (8.0 mg, 53%) having the following characteristics.