Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+].Cl[C:21]([CH:23]([CH2:35][CH2:36][CH2:37][CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22]>CCOCC.CCOCCOCCO.O>[N+:1](=[CH:3][C:21]([CH:23]([CH2:35][CH2:36][CH2:37][CH:38]([O:44][C:45](=[O:47])[CH3:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:22])=[N-:2]
Reactant: C=[N+]=[N-]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)Cl)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCCOCCO
Solvent: O
Solvent: CCOCC
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)C=[N+]=[N-])OC(C)=O

Procedure:
Diazomethane (6 g., 0.143 mole) is generated via dropwise addition of a solution of Diazald ® (43 g.) in ether (400 ml.) over 45 minutes to a warm (65%), stirred solution of potassium hydroxide (12 g., 0.214 mole) in carbitol-water (7:2, 90 ml.). The resulting yellow, ethereal diazomethane distillate is cooled to 0° and treated with a solution of ethyl 8-chlorocarbonyl-12-acetoxyheptadecanoate (8.1 g., 0.02 mole) (Example 7, Step D), in ether (40 ml.) added over a period of 15 minutes.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:25])[N:11]([CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:32][CH:31]=[CH:30]2.O.[C:53]([OH:57])(=[O:56])[CH:54]=O>>[C:48]([O:47][C:45]([N:37]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[C:33]1[C:34]2[C:29](=[CH:28][C:27]([NH:26][CH:54]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH2:13][N:11]([CH3:12])[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=4)=[O:25])=[CH:17][CH:18]=3)[C:53]([OH:57])=[O:56])=[CH:36][CH:35]=2)[CH:30]=[CH:31][N:32]=1)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Reactant: CN(CCCc1ccc(B(O)O)cc1)C(=O)Nc1cccc(C#N)c1
Solvent: O
Product: CN(CCCc1ccc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc1)C(=O)Nc1cccc(C#N)c1
Yield: 41 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 22D (146 mg, 0.43 mmol) was reacted with Intermediate 1 and glyoxylic acid monohydrate to afford 22E (124 mg, 41%) as a yellow solid. MS (ESI) m/z 709.08 (M+H)+.
Reaction SMILES: [BH4-].[Li+].[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:22](=[O:25])[CH2:23][Cl:24])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.ClCCl.O>C1COCC1>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH:22]([OH:25])[CH2:23][Cl:24])=[C:15]2[C:20]=1[NH:19][C:18](=[O:21])[CH:17]=[CH:16]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(CCl)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: O=c1ccc2c(C(O)CCl)ccc(OCc3ccccc3)c2[nH]1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
238 mL of a 2 molar solution of lithium borohydride in THF are added dropwise to 52 g (159 mmol) 8-benzyloxy-5-(2-chloro-acetyl)-1H-quinolin-2-one in 650 mL THF at 0° C. It is stirred for two hours at 0° C., then heated to ambient temperature, combined with 200 mL dichloromethane and 75 mL water and stirred for a further hour. The precipitated solid is suction filtered and the organic phase of the filtrate is separated off and freed from the solvent. The residue is combined with the solid from the preceding filtration and repeatedly stirred with diethyl ether and THF. Yield: 51.6 g (99%); mass spectroscopy [M+H]+=330/32.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([N:17]4[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]4)[CH:14]=[CH:13][CH:12]=3)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.CC([NH:41][C:42]([NH2:44])=[O:43])(C)C>>[NH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:15]2[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[CH:6][N:7]=[C:2]([NH:41][C:42]([NH2:44])=[O:43])[CH:3]=4)[NH:8][N:9]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:18]1
Reactant: CC(C)(C)NC(N)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2cccc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)n2)C1
Product: NC(=O)Nc1cc2c(-c3cccc(N4CCC[C@H](N)C4)n3)n[nH]c2cn1
Yield: 23 %

Procedure:
Following the Buchwald-Hartwig procedure of Example 224, tert-butyl (3S)-1-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ylcarbamate and (1,1-dimethylethyl)urea were reacted and deprotected by the procedure of Example 229. The mixture was purified via reverse phase HPLC using a gradient of MeOH in water with 0.1% NH4OH to afford 20 mg (23%) of 298 over three steps. ESI MS m/z 353.2 (M+1). 1H NMR (400 MHz, DMSO): 9.14 (s, 1H), 8.96 (s, 1H), 8.75 (s, 1H), 8.40 (s, 2H), 7.63 (t, J=8.0 Hz, 1H), 7.45 (d, J=7.4 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 6.48 (s, 2H), 4.92 (d, J=11.4 Hz, 1H), 4.05 (d, J=12.9 Hz, 1H), 3.09 (m, 1H), 2.94-2.77 (m, 2H), 2.54 (s, 2H), 2.05 (d, J=9.7 Hz, 1H), 1.84 (d, J=13.1, Hz, 1H), 1.64-1.42 (m, 2H)
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17](I)[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:1]1([C:7]2[O:21][C:18]3[CH:19]=[CH:20][C:15]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:16][C:17]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(-c2ccccc2)cc1I
Reactant: C#Cc1ccccc1
Product: c1ccc(-c2ccc3oc(-c4ccccc4)cc3c2)cc1

Procedure:
The general procedure was used to convert phenylacetylene and 4-phenyl-2-iodophenol to the title product. Purification by flash chromatography (10% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (427 mg, 79% yield). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.53, 2H), 7.78-7.75 (m, 1H), 7.67-7.33 (m, 10H), 7.07 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 156.56, 154.49, 141.63, 136.61, 130.37, 129.74, 128.79, 128.73, 128.62, 127.41, 126.86, 124.93, 123.98, 119.36, 111.25, 101.45. Anal. Calcd. For C20H14O: C, 88.86; H, 5.22. Found C, 88.99; H, 5.28. m.p.: 166-167° C. (lit., 8166-168° C.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:38]
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]O)=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S(Cl)([Cl:27])=O>N1C=CC=CC=1.O1CCCC1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][Cl:27])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Cn1c(CO)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 6-bromo-3-hydroxymethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (8.7 g, 22.5 mmol) and pyridine (5 drops) in tetrahydrofuran (30 mL) and toluene (30 mL) was added thionyl chloride (3.4 mL, 47.3 mmol). The obtained mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6-bromo-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (8.2 g, 90%) as crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=O)[CH2:19][C:20](=O)[C:21]([O:23][CH3:24])=[O:22])=[N:16][CH:17]=1.C([O-])(O)=O.[Na+]>CO.CCOC(C)=O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[Cl:2])[N:10]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=2)=[N:16][CH:17]=1
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)CC(=O)c1ccc(Br)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccc(Br)cn2)n(-c2ccccc2Cl)n1
Temperature: 120 °C
Yield: 12.7 %

Procedure:
A mixture of (2-chlorophenyl)hydrazine hydrochloride (1.1 g, 6.1 mmol) and methyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate (1.7 g, 6.0 mmol) in MeOH (30 mL) was divided into two microwave reaction vessels. Each reaction vessel was then heated in the microwave at 120° C. for ten minutes. LC/MS analysis at this time showed the reaction to be essentially complete. The solutions were concentrated under reduced pressure to afford a dark brown semi-solid. This material was taken up in EtOAc and saturated aqueous NaHCO3. The layers were separated and the basic aqueous was extracted with EtOAc (3×). Combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford a dark oil. This crude product was purified by flash column chromatography eluting with a gradient from 0% to 100% EtOAc in hexane to afford methyl 5-(5-bromopyridin-2-yl)-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate (300 mg, 13% yield) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].Cl[C:9](Cl)(Cl)[CH2:10][N+:11]([O-:13])=[O:12].Cl>CO.ClCCl.O>[N+:11]([CH:10]=[C:9]1[NH:1][CH2:2][CH2:3][CH2:4][S:5]1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])CC(Cl)(Cl)Cl
Reactant: NCCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Into 50 ml of methanol were added 8.1 g of 1-amino-3-propanethiol and 5.0 g of caustic soda, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, a solution of 5.4 g of 2,2,2-trichloro-1-nitroethane diluted in 20 ml of methanol was added dropwise slowly over 15 minutes, and the reaction was carried out for one hour. The reaction was exothermic and the liquid temperature was maintained at lower than 10° C. (about 8° C.). After the reaction, the reaction mixture was neutralized to pH 7 with 6 N aqueous hydrochloric acid, and then with addition of 50 ml of water, extraction with 100 ml of dichloromethane was repeated four times. The extracts were concentrated to give 2.91 g of tetrahydro-2-(nitromethylene)-1,3-thiazine (yield: 60.1%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@:13]2([CH2:23][CH2:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:37]4[CH:38]=[N:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:17][CH:18]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.327 min, m/z=542.1; 1H NMR (CD3OD) 1.33 (m, 1H), 1.58 (d, 3H), 1.66 (m, 1H), 1.98 (m, 2H), 2.20-2.39 (m, 2H), 2.47 (m, 1H), 2.87 (s, 3H), 2.99 (m, 2H), 3.15 (m, 1H), 3.96 (s, 3H), 5.60 (m, 1H), 6.87 (d, 1H), 7.12 (m, 4H), 7.36 (m, 4H), 7.87 (d, 1H), 8.29 (s, 1H).
Reaction SMILES: F[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:13])[CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:6]([C:5]1[C:4]([CH3:13])=[CH:3][C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1C#N
Temperature: 80 °C
Yield: 110 %

Procedure:
A solution of 4-fluoro-2-methyl-5-nitrobenzonitrile (D90) (3 mmol, 540.3 mg) in dimethylformamide (20 mL) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (3 mmol, 600.9 mg, 1 eq) and diisopropylethylamine (3 mmol, 387.6 mg, 1 eq) under argon at room temperature and then heated at 80° C. overnight. The mixture was then concentrated under reduced pressure then treated with 10% aqueous sodium carbonate solution and extracted with ether/ethyl acetate. The organics were dried and concentrated under reduced pressure to give the title compound as a solid (3.3 mmol, 1.19 mg, >100% yield). M+H 304.97 for main fragment (loss of tert-butyl group).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][C:10]=2C)[NH:5][C:4]=1[CH3:13])#N.[CH2:14]([Cl:23])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].[C:24](#[N:26])C>>[ClH:23].[C:24]([CH2:1][C:3]1[C:11]2[C:6]([N:7]([CH2:14][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:16])[CH:8]=[CH:9][CH:10]=2)=[N:5][C:4]=1[CH3:13])#[N:26]
Reactant: CC#N
Reactant: Cc1[nH]c2nccc(C)c2c1C#N
Reactant: O=C(CCl)c1ccccc1
Product: Cc1nc2n(CC(=O)c3ccccc3)cccc-2c1CC#N
Product: Cl
Yield: 58 %

Procedure:
A solution of 1.0 g (5.8 mmol) of 3-cyano-methyl-2-methyl pyrrolo[2,3-b]pyridine and 1.08 g (7.0 mmol) of phenacyl chloride in 50 ml acetonitrile was refluxed for 14 h. Working up in the same manner as described in example 17 gave 0,5 g 58% of the desired title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=4)[C:11]=3[CH:25]=2)=[N:4][N:3]=1.[OH-].[Na+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=4)[C:11]=3[CH:25]=2)=[N:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)cc4)c3c2)o1
Temperature: 60 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
A mixture of methyl 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoate (204 mg, 0.610 mmol), 1 M aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (6 mL) and methanol (6 mL) was stirred at 60° C. for 24 hr. After cooling, the reaction mixture was poured into water, and acidified with 1M hydrochloric acid. The precipitate was collected by filtration, dried, and recrystallized from ethanol to give the title compound (163 mg, yield 83%) as colorless crystals.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O>CO.Cl.O>[Cl:6][CH2:7][CH2:8][CH2:9][C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: NNC(N)=S
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
Thiosemicarbazide (9.11 g, 0.1 mol) was added under nitrogen to a solution of 4-chlorobutyrophenone (16 mL, 0.1 mol) in 350 mL of methanol plus 27 mL of 1 N HCl plus 25 mL of water. After approximately 30 minutes of stirring at room temperature, all of the solid had dissolved. The reaction was then stirred at room temperature for 24 hours (overnight). The solid that had formed was collected by filtration and dried under high vacuum to give 17.41 g (68%) of the title compound as a white solid, mp 128-130° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])[CH2:5][C:6]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1c(Cl)cccc1Cl
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1c(Cl)cccc1Cl
Temperature: 110 °C

Procedure:
A mixture of 2-(2,6-dichloro-phenyl)-3-(2,4-dichloro-pyrimidin-5-yl)-propionic acid methyl ester (0.20 g, 0.53 mmol) (from Example 2a supra) and aniline (2.0 ml) (Aldrich) was heated at 110° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2,6-dichloro-phenyl)-propionic acid methyl ester as a brown caramel which was used in the next step without further purification. (Yield 0.18 g, 69.3%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[CH2:9]=O.[Br-].[Mg+2].[Br-]>C(#N)C>[S:1]1[C:2]2[CH2:6][CH2:7][O:8][CH2:9][C:3]=2[CH:4]=[CH:5]1
Reactant: C=O
Reactant: OCCc1cccs1
Agent: [Br-]
Agent: [Mg+2]
Solvent: CC#N
Product: c1cc2c(s1)CCOC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
10.0 g of 2-thiopheneethanol, 5.9 g of paraformaldehyde, and 28.7 g of magnesium bromide were added to 780 mL of acetonitrile, and the resulting mixture was refluxed for 24 hours. The reaction product solution was cooled to room temperature and concentrated by evaporation under reduced pressure. To the residue, 100 mL of water and 150 mL of n-hexane were added, and the resulting mixture was stirred for 5 minutes. The organic layer was separated and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 4.7 g (yield of 43%) of the title compound, of which analysis data were the same as obtained in Example 14.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].P(OC)(OC)(O[CH3:18])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH3:18])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: COP(=O)(OC)OC
Product: CCOC(=O)c1cn(C)nc1C(F)(F)F
Temperature: 180 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A mixture of 2.08 g of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (10 mmol) and 2.3 ml of trimethyl phosphate (20 mmol) is stirred at a temperature of 180° C. for 16 hours. 200 ml of an ice-water mixture are then added. The resulting reaction product is filtered, washed with water and dissolved in 50 ml of ethyl acetate. The organic phase is washed twice with 50 ml of saturated sodium chloride solution each time and dried over sodium sulfate and concentrated by evaporation. 1.9 g (86% of theory) of 3-trifluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester are obtained in the form of crystals (m.p. 55-57° C.).
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].CO[C:11](=[O:32])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[C:21]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[N:22][O:23][CH:24]=2)=[N:14][CH:13]=1.O>O1CCOCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:21]2[C:20]([CH2:19][O:18][C:15]3[CH:16]=[CH:17][C:12]([C:11]([NH:8][CH:5]([CH3:7])[CH3:6])=[O:32])=[CH:13][N:14]=3)=[CH:24][O:23][N:22]=2)=[CH:30][CH:29]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)NC(=O)c1ccc(OCc2conc2-c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 1.17 mL, 2.3 mmol) was added dropwise (exothermic) to a solution of isopropylamine (2.3 mmol) in dioxane (15 mL) and the resulting mixture was stirred at room temperature for 1.5 h. Then 6-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.58 mmol) was added. The resulting mixture was then heated at 85° C. for 2 h and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=2:1 to 1:1) afforded the title compound (120 mg, 56%) which was obtained as a white solid. MS: m/e=372.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:21]1([CH2:20][CH2:19][CH2:18][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
To an ice-cooled solution of ethyl 4-hydroxybenzenepropanoate (0.40 g, 2.1 mmol) in N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.11 g, 2.7 mmol), and the mixture was stirred for 30 min. 1-Bromo-3-phenylpropane (0.53 g, 2.7 mmol) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=18:1) to give the title compound (0.29 g, yield 46%). oil.