Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)[CH:7]=[CH:6][C:5]=1[Cl:16].[OH-].[Na+]>C(O)(C)(C)C>[Cl:16][C:5]1[CH:6]=[CH:7][C:8]([C:10]2[N:11]=[C:12]([CH3:15])[S:13][CH:14]=2)=[CH:9][C:4]=1[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(-c2csc(C)n2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(-c2ccc(Cl)c(C(=O)O)c2)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture of 2-chloro-5-(2-methyl-thiazol-4-yl)-benzoic acid methyl ester (10 mg, 0.04 mmol) and sodium hydroxide (80 μL, 1M aqueous, 0.08 mmol) in tert-butanol (1 mL) was stirred at room temperature for 3 d. The mixture was concentrated to dryness in vacuo, dissolved in water (5 mL), acidified to pH 6 (1M HCl) and extracted with ethyl acetate. The combined organic layers were washed with water, and brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound (7 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[SH:31][CH2:32][CH2:33][OH:34]>CN(C=O)C.C(OCC)(=O)C>[OH:34][CH2:33][CH2:32][S:31][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2Cl)CC1
Reactant: OCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])ccc2SCCO)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.2 %

Procedure:
To a stirred solution of tert-butyl 4-(2-chloro-5-nitrophenylamino)piperidine-1-carboxylate (1.25 g, 3.51 mmol) in DMF (10 mL) were added sequentially potassium carbonate (0.971 g, 7.03 mmol) and 2-mercaptoethanol (0.493 mL, 7.03 mmol). The resulting mixture was stirred at 60° C. for 1 hour, after which TLC analysis (2:3 ethyl acetate:hexanes) showed that the reaction was complete. The mixture was then diluted with ethyl acetate and washed sequentially with water and saturated sodium carbonate (3×). The organic phase was dried, filtered, concentrated, and then chromatographed in 2:3 ethyl acetate:hexanes, giving the desired product (1.202 g, 86%) as an orange foam. 1H NMR (DMSO-d6) δ 7.51 (d, J=8.4 Hz, 1H), 7.43-7.37 (m, 2H), 5.40 (d, J=8.1 Hz, 1H), 5.06 (t, J=5.4 Hz, 1H), 3.95-3.86 (m, 2H), 3.75-3.60 (m, 1H), 3.59-3.50 (m, 2H), 3.01-2.85 (m, 4H), 1.94-1.83 (m, 2H), 1.49-1.29 (m, 11H); ESI-MS (m/z, %): 420 (M+Na, 22), 342 (100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[O:13][CH2:14][C:15]#[N:16].C(O)(C)C>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[O:13][CH2:14][C:15]#[N:16])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: N#CCOc1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: CC(C)O
Product: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Yield: 53.9 %

Procedure:
Into an 80 ml microwave vessel was added 2,4,5-Trichloro-pyrimidine (1.86 g, 0.01 mol), (2-Amino-phenoxy)-acetonitrile (1.500 g, 0.01 mol), and N,N-DIEA (1.96 g, 0.015 mol), Isopropyl alcohol (20 mL, 0.3 mol). The reaction was microwaved at 120° C. for 60 minutes. The resulting orange suspension was filtered and the solid was washed with Isopropyl alcohol to afford a light pink solid (1.59 g, 53%). HPLC purity 95%.
Reaction SMILES: Cl.O1CCOCC1.[CH:8]([C:11]1[C:12]([O:41]COC)=[CH:13][C:14]([O:37]COC)=[C:15]([C:17]2[N:18]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[C:19](=[O:22])[NH:20][N:21]=2)[CH:16]=1)([CH3:10])[CH3:9]>CO>[OH:37][C:14]1[CH:13]=[C:12]([OH:41])[C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][C:15]=1[C:17]1[N:18]([C:23]2[CH:24]=[CH:25][C:26]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]3)=[CH:27][CH:28]=2)[C:19](=[O:22])[NH:20][N:21]=1
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=O)n1-c1ccc(CN2CCN(C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)c1cc(-c2n[nH]c(=O)n2-c2ccc(CN3CCN(C)CC3)cc2)c(O)cc1O
Temperature: 40 °C
Reaction time: 1 h

Procedure:
At room temperature, 4 N hydrochloric acid/1,4-dioxane solution (5 mL) was added to a methanol (5 mL) solution of 5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methyl piperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (F652-09, 644 mg, 1.26 mmol). After stirring at 40° C. for 1 hour, the solvent was distilled off under reduced pressure. Methanol was added to the crude product thus obtained, and the resulting suspension was stirred at room temperature. The precipitated solid was collected by filtration to obtain 5-(2,4-dihydroxy-5-isopropylphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (OH-a13) dihydrochloride (white solids).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:17]([N:19]([CH:33]([CH3:35])[CH3:34])[C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[O:18])[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=2[O:3]1.[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42]Br)[CH3:38].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:37]([O:39][C:40](=[O:44])[CH2:41][CH2:42][N:6]1[C:5]2[CH:9]=[C:10]([C:17]([N:19]([CH:33]([CH3:34])[CH3:35])[C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[O:18])[C:11]([C:13]([F:14])([F:15])[F:16])=[CH:12][C:4]=2[O:3][C:2]([CH3:36])([CH3:1])[C:7]1=[O:8])[CH3:38]
Reactant: CCOC(=O)CCBr
Reactant: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C)C(=O)N2)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21

Procedure:
To tert-Butyl (3R)-3-[{[2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (460 mg) were added 3-bromopropionic acid ethyl ester (0.19 ml), potassium carbonate (298 mg) and acetonitrile (5 ml), and the mixture was refluxed for 5 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (350 mg) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[NH:4][C:5](=[O:14])[N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:7]=1[NH2:8].[CH:16](Cl)(Cl)Cl.CCOCC>C(O)=O>[CH2:9]([N:6]1[C:7]2[N:8]=[CH:16][NH:1][C:2]=2[C:3](=[O:15])[NH:4][C:5]1=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: ClC(Cl)Cl
Reactant: CCCCCn1c(N)c(N)c(=O)[nH]c1=O
Solvent: CCOCC
Solvent: O=CO
Product: CCCCCn1c(=O)[nH]c(=O)c2[nH]cnc21

Procedure:
37.4 g of 5,6-diamino-1-pentyl-2,4-(1H,3H)-pyrimidinedione (XXXIX) was refluxed in 50 ml of formic acid for 2 h. 50 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 36.8 g. The amide was refluxed in 50 ml of 5N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 1.8 l of ethanol. Yield 18.3 g (XXXVIII) NMR (see Table I).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17].C([O-])([O-])=O.[Na+].[Na+]>B(F)(F)F.CCOCC>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:13](=[O:15])[CH2:12][CH:9]1[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)C1CCC(CC(=O)O)CC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C1CCC(CC(=O)c2ccc(O)cc2O)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 2-(4-(ethoxycarbonyl)cyclohexyl)acetic acid (700 mg, 11.6 mmol) in BF3-Et2O (10 ml) was added resorcinol (1.5 g, 14.0 mmol). The solution was stirred at 85° C. overnight, poured into Na2CO3 solution (2N, 20 ml), extracted with EtOAc (30 ml×3), washed with brine, dried over Na2SO4, filtrated and concentrated to afford 3 g of yellow oil, which was purified by silica gel column (PE/EtOAc=3/1) to afford 400 mg of Intermediate C. MS (ESI): m/z 307.1[M+1]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)#[N:14].C(N(CC)CC)C>C(#N)C>[C:13]([C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:34])[NH:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=3)(=[O:31])=[O:32])=[CH:26][CH:25]=2)[CH:18]=[CH:19][CH:20]=1)#[N:14]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3cccc(C(F)(F)F)c3)cc2)c1
Reaction time: 72 h
Yield: 97.3 %

Procedure:
3-Trifluoromethylbenzylamine (0.52 g, 1 eq.) was added to a solution of 4-[3-(3-cyanophenyl)-ureido]-benzenesulfonyl chloride (1 g, 1 eq.) and triethylamine (1.05 ml, 1.6 eq.) in acetonitrile (10 ml) under inert atmosphere. The mixture was stirred for 3 d, concentrated in vacuo and water was added. The resulting precipitate was filtered off and dried in vacuo to yield 1.37 g (97%) of 4-[3-(3-cyanophenyl)-ureido]-N-(3-trifluoromethylbenzyl)-benzenesulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]([OH:16])=O)[C:8](=[O:17])[CH:7]=[CH:6]2)#[CH:2].[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH2:24])[S:22][CH:23]=1>>[Br:18][C:19]1[C:20]([C:25]2[NH:29][N:28]=[CH:27][N:26]=2)=[C:21]([NH:24][C:14](=[O:16])[CH2:13][N:9]2[C:10]3[C:5](=[CH:4][C:3]([C:1]#[CH:2])=[CH:12][CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:17])[S:22][CH:23]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: C#Cc1ccc2c(ccc(=O)n2CC(=O)O)c1
Product: C#Cc1ccc2c(ccc(=O)n2CC(=O)Nc2scc(Br)c2-c2ncn[nH]2)c1

Procedure:
The title compound was synthesized from 2-(6-ethynyl-2-oxoquinolin-1(2H)-yl)acetic acid and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine according to protocol A. Retention time (min)=6.563, method [7], MS(ESI) 454.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.07 (d, J=9.35 Hz, 1H), 8.01-7.97 (m, 1H), 7.68-7.63 (m, 1H), 7.50 (d, J=8.80 Hz, 1H), 7.30 (s, 1H), 6.80 (d, J=9.9 Hz, 1H), 5.27 (s, 2H), 4.23 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[S:17][C:16]([S:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:15][N:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[S:17][C:16]([S:18][CH2:19][C:20]([OH:22])=[O:21])=[N:15][N:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2nnc(SCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1c(OCCCSc2nnc(SCC(=O)O)s2)ccc(C(C)=O)c1O
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
To a mixture of 4.2 g of ethyl [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetate obtained in Example 14 and 30 ml of methanol was added 20 ml of an aqueous solution of 5% sodium hydroxide and the mixture was stirred for 30 minutes. Then, 30 ml of water was added to the reaction mixture and methanol was removed under reduced pressure. The residue thus formed was washed with ethyl acetate, acidified with diluted hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus formed was recrystallized from 90% ethanol to provide 3.07 g of [[5-[[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl]thio]-1,3,4-thiadiazol-2-yl]thio]acetic acid. The properties of the compound thus obtained were same as those of the compound obtained in Example 21.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:38][C:39]1[S:40][CH:41]=[CH:42][CH:43]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:28]1[CH:29]=[N:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=1)[CH2:22][C:23]1[CH:24]=[N:25][N:26]([CH2:38][C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)[CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: ClCc1cccs1
Product: CC(C)c1ccc(N(Cc2cnn(Cc3cccs3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 87.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.96 g) and 2-(chloromethyl)thiophene (0.25 g) as a starting material, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.95 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 133, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-thienylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.41 g) was obtained. melting point: 125-129° C.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH:4]1[C:9](O)=O)=O.C(OC(=O)C)(=O)C.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[C:20]#[CH:21]>>[CH2:24]([O:23][C:19]([C:20]1[CH:9]=[CH:4][N:3]2[CH2:8][CH2:7][O:6][CH2:5][C:21]=12)=[O:22])[CH3:25]
Reactant: O=CN1CCOCC1C(=O)O
Reactant: C#CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1ccn2c1COCC2
Temperature: 120 °C
Yield: 37 %

Procedure:
To a mixture of 4-formyl-morpholine-3-carboxylic acid (Comp. No. 1) (43 g, 0.295 mol) and acetic anhydride (410 g, 4 mol) was added ethyl propiolate (190 g, 1.94 mol). The resulting mixture was heated slowly to 120° C., which was accompanied by gas evolution. After heating for 2 h at 120° C., the resulting mixture was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluting with up to 25% ethyl acetate in heptane) to give 21.4 g (37%) of pure 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ethyl ester. LC/MS (method 4): Rt=1.10 min; m/z=196.1 (M+H+).
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[N:11][CH:10]=[CH:9][N:8]=1.S(O[CH:27]([CH2:31][C:32]#[CH:33])[C:28](=O)[CH3:29])(C)(=O)=O>C(O)C>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][O:13][C:12]1[C:7]2[N:8]([C:27]([CH2:31][C:32]#[CH:33])=[C:28]([CH3:29])[N:6]=2)[CH:9]=[CH:10][N:11]=1
Reactant: C#CCC(OS(C)(=O)=O)C(C)=O
Reactant: Cc1ccccc1COc1nccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C#CCc1c(C)nc2c(OCc3ccccc3C)nccn12
Yield: 3.8 %

Procedure:
Sodium bicarbonate (2.73 g) was added to a solution of 2-amino-3-(2-methylbenzyloxy)pyrazine (3.5 g) and 3-mesyloxy-5-hexyn-2-one (6.18 g) in ethanol (35 ml) and the mixture was refluxed for 12 hours. The mixture was poured into an aqueous solution of sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (200 g) with a mixture of chloroform and methanol (50:1) as an eluent to give 8-(2-methylbenzyloxy)-3-(2-propynyl)-2-methylimidazo[1,2-a]pyrazine (0.182 g).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:23])[CH2:7][C:8]([NH:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:13][N:12]=1)=[O:9])C.C1COCC1>O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:13][N:12]=[C:11]([NH:10][C:8](=[O:9])[CH2:7][C:6]([OH:23])=[O:5])[CH:15]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC(=O)Nc1cc(-c2ccc(F)cc2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
NaOH (34 mg, 8.5 mmol) was added to a solution of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid ethyl ester (292 mg, 1.0 mmol) in the mixture of THF (13 mL) and H2O (13 mL) and stirred for 1 hr at room temperature. The reaction mixture was concentrated and the obtained residue was diluted with water, acidified with concentrated HCl, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated to afford 40 mg (90.9% Yield) of N-[5-(4-fluoro-phenyl)-isoxazol-3-yl]-malonamic acid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([I:14])=[C:10]([CH3:13])[CH:11]=2)[CH:6]=[N:5]1)(=O)C.N>C1COCC1>[I:14][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[CH3:13])[NH:4][N:5]=[CH:6]2
Reactant: CC(=O)n1ncc2cc(I)c(C)cc21
Agent: N
Solvent: C1CCOC1
Product: Cc1cc2[nH]ncc2cc1I
Yield: 100.8 %

Procedure:
1-Acetyl-5-iodo-6-methylindazole (1.5 g, 5.0 mmol) was stirred with ammonia (7 M in methanol, 4 mL) in methano/THF (2/1, 15 mL) for 1 h. The solution was evaporated to give the subtitle compound (1.3 g, 100%) as an off-white powder.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9]CC)=[O:8])=[CH:5][N:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][N:6]=2)=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cnc(-c2ccncc2)s1
Reaction time: 0.33 h

Procedure:
A mixture of ethyl 2-bromo-1,3-thiazole-5-carboxylate (0.095 mL, 0.64 mmol), pyridine-4-ylboronic acid (0.094 g, 0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.007 g, 0.006 mmol), and potassium carbonate (0.263 g, 1.91 mmol) in 1,4-dioxane (10 mL) and water (0.5 mL) was subjected to MWI at 160° C. for 20 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic solutions were combined, acidified and concentrated. The residue was dissolved in EtOAc and brine was added. The organic solution was separated, dried over Na2SO4, filtered and concentrated to give 2-pyridin-4-yl-1,3-thiazole-5-carboxylic acid which was used without further purification. LCMS: (FA) ES+ 207.
Reaction SMILES: [Br:1]Br.[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O.[OH-].[Na+]>C(O)(=O)C>[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:1])=[CH:7][CH:6]=1
Reactant: CNc1ccccc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 102.2 %

Procedure:
A solution of 179 g of bromine in 120 ml of acetic acid was added at less than 40° C. over 45 minutes under an inert atmosphere to a mixture of 120 g of N-methyl-aniline and 600 ml of acetic acid and the mixture was stirred for 75 minutes and then was cooled to room temperature and poured into a mixture of ice and water. The pH of the mixture was adjusted to 10 by addition of sodium hydroxide and the mixture was extracted with methylene chloride. The organic phase was washed with aqueous saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure to obtain 213 g of N-methyl-4-bromo-aniline.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=2[CH2:37][CH2:38][CH3:39])[C:10]=1[CH2:40][CH2:41][CH3:42])C.[OH-].[Na+]>CO>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])=[C:10]([CH2:40][CH2:41][CH3:42])[C:11]=1[O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[C:29]([OH:36])[C:28]=1[CH2:37][CH2:38][CH3:39])(=[O:17])[CH3:16]
Reactant: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCOCCCOc2c(C(C)=O)ccc(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Yield: 93 %

Procedure:
A solution of 2.06 g (0.0034 mole) of 4-[4-acetyl-3-[3-[3(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid ethyl ester in 50 ml of methanol and 17 ml (0.017 mole) of 1.0N sodium hydroxide was stirred at reflux for 2 hours. Most of the solvent was removed and the pH of the residue was adjusted to 2.0 The product was extracted with methylene chloride. The extract was washed with water, dried (magnesium sulfate) and concentrated in vacuo to give 1.81 g (92% yield) of 4-[4-acetyl-3-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-propylphenoxy]butanoic acid as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.CN(C(O[N:27]1N=N[C:29]2[CH:30]=[CH:31][CH:32]=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11]([CH:14]=[CH:15][C:16]([NH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:33]=3)=[O:18])=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1cnc(-c2ccc(F)cc2)nc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cnc(-c2ccc(F)cc2)nc1)Nc1ccccn1

Procedure:
The N-substituted 3-[2-(4-fluoro-phenyl)-pyrimidin-5-yl]-acrylamides of the formula Ik, which are listed in Table 8, were prepared as described in Example 116(d) from 110 mg (0.45 mmol) of 3-[2-(4-fluoro-phenyl)-pyrimidin-5-yl]-acrylic acid, 0.9 mmol of the respective amine, 171 mg (0.45 mmol) of HATU and 136.7 mg (1.35 mmol) of triethylamine.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.[C:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21](Cl)=[O:22])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].O>[Na]>[C:9]([C:13]1[S:17][C:16]([CH:18]2[CH2:20][CH:19]2[C:21]([N:4]2[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]2)=[O:22])=[CH:15][CH:14]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)c1ccc(C2CC2C(=O)Cl)s1
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Na]
Solvent: O
Product: C[C@@H]1CN(C(=O)C2CC2c2ccc(C(C)(C)C)s2)C[C@H](C)O1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
cis-2,6-Dimethylmorpholine (6.6 g, 0.057 mol) was added dropwise to a solution of 2-(5-t-butylthiophen-2-yl)-cyclopropanecarbonyl chloride (2.50 g, 0.01 mol) in sodium dried ether (20 ml) at 10° C. and after complete addition the solution was stirred at 20° C. for 3 hours. The reaction mixture was poured into water and extracted with diethyl ether (2×75 ml). The ethereal extracts were washed with water, dried over anhydrous sodium sulphate, and the solvent removed to give 2-(5-t-butylthiophen-2-yl)-cyclopropanecarbonyl-2,6-cis-dimethylmorpholine as a yellow oil. This oil was separated by column chromatography (silica eluted with petroleum ether/ethyl acetate 1:1) to give 2-(5-t-butylthiophen-2-yl)-trans-cyclopropanecarbonyl)-2,6-cis-dimethylmorpholine (1.70 g, 53%) and 2-(5-t-butylthiophen-2-yl)-cis-cyclopropanecarbonyl)-2,6-cis-dimethylmorpholine (0.94 g, 29%).