Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][C:6]([NH2:8])=[O:7])=[O:4].[Na].[CH:10](OCC)=O.Cl>O.C1C=CC=CC=1.C(O)C>[CH3:1][N:2]1[CH:10]=[N:8][C:6](=[O:7])[NH:5][C:3]1=[O:4]
Reactant: CNC(=O)NC(N)=O
Reactant: CCOC=O
Agent: Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: Cn1cnc(=O)[nH]c1=O
Temperature: 60 °C
Yield: 90 %

Procedure:
A reaction mixture consisting of 70.2 gm. (0.6 mole) of the 1-methylbiuret prepared in Part A above, 3.5 l. absolute ethanol, and 200 ml. benzene is heated to the reflux temperature with stirring in a 5-l., three-necked flask fitted with a reflux condenser, a stirrer, and thermometer. A top of the condenser is fitted with a nitrogen outlet, but no water is run through the condenser. After removing the nitrogen outlet, 200 ml. of the medium is allowed to distill through the condenser. The reaction mixture is then cooled to 60° C., before 28 gm. (1.2 mole) of sodium metal is added slowly over an interval of five (5) minutes. A white solid precipitates, but stirring is continued until all the sodium is dissolved. At this point, 104 gm. (1.4 mole) of ethyl formate is added in one portion and the reaction mixture is again heated to the reflux temperature (about 75° C.) and refluxed for three (3) hours. The reaction mixture is cooled to about 30° C. and hydrogen chloride gas is blown over the surface until an acid pH is attained. The reaction mixture is again heated at the reflux temperature for 15 minutes. The hot mixture is filtered through a diatomaceous earth filter and the filter is washed with hot ethanol. The filtrate and washings are concentrated to a volume of 200 to 300 ml. by removing medium by evaporation under reduced pressure. The concentrate is cooled to 5° C. and set aside at that temperature for several hours for crystallization. The crystals are collected on a filter and washed with cold ethanol. After, drying the crystals under reduced pressure there is obtained 69 gm. (90% yield) of 1-methyl-5-azauracil having a melting range from 200° to 205° C. A sample recrystallized three times from ethanol has a melting point of 213° to 214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH2:10][CH2:11]Cl)[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[CH2:6][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:10]2
Reactant: Nc1ccccc1
Reactant: ClCCc1cc(Cl)ccc1CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)CCN(c1ccccc1)C2

Procedure:
4-chloro-2-(2-chloroethyl)benzyl chloride (5 g), aniline (2.1 g) and triethylamine (5.7 g), were dissolved in chloroform (40 ml) and the mixture heated at reflux for 18 hr. The reaction mixture was cooled and washed with 2M sodium hydroxide solution (100 ml), 2M hydrochloric acid (100 ml) and water (100 ml), then dried (sodium sulphate) and evaporated to dryness in vacuo. The residue was chromatographed on silica gel to give the product, 6-chloro-2-phenyl-1,2,3,4-tetrahydroisoquinoline m.pt. 67°-70°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:43]([NH2:49])[CH:44]1[O:48][CH2:47][CH2:46][CH2:45]1>O1CCCC1.O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:49][CH2:43][CH:44]4[CH2:45][CH2:46][CH2:47][O:48]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NCC1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCC1CCCO1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.7 %

Procedure:
The title compound was prepared as described in Example 76. To a solution of 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.200 g, 0.781 mmol) in tetrahydrofuran (5 mL) was added 1-hydroxybenzotriazole hydrate (0.316 g, 2.34 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.449 g, 2.34 mmol), tetrahydrofurfurylamine (0.242 mL, 2.34 mmol) and N,N-dimethylformamide (2 mL). The solution was stirred for 16 h at room temperature. Water (40 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (10–90% acetonitrile/water). The pure fractions were made basic with ammonium hydroxide, the solution evaporated under reduced pressure, diluted with water and filtered which gave the title compound (0.198 g, 74% yield): 1H NMR (DMSO-d6) δ 13.43 (s, 1H), 8.71 (t, 1H), 8.56 (m, 1H), 8.08 (AB quartet, 2H), 7.92 (dd, 1H), 7.62 (dd, 1H), 7.40 (t, 2H), 4.01 quartet, 1H), 3.79 (q, 1H), 3.63 (q, 1H), 3.36 (m, 2H), 1.97 (m, 1H), 1.83 (m, 2H), 1.62 (m, 1H); ES-MS (m/z) 340 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][C:5]1([CH:11]([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](O)=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH2:23]([N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:11]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][C:3]2[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=2[NH:1][C:12]1=[O:13])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1ccccc1OC1(C(C(=O)O)N(Cc2ccccc2)Cc2ccccc2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Nc2ccccc2OC2(CCCCC2)C1N(Cc1ccccc1)Cc1ccccc1
Yield: 63.4 %

Procedure:
A mixture of 2-(1-(2-Aminophenoxyl)cyclohexyl)-2-(dibenzylamino)acetic acid (0.6365 g, 1.43 mmol, Eq: 1.00), HOBT.H2O (307 mg, 2.00 mmol, Eq: 1.4) and EDCI (274 mg, 1.43 mmol, Eq: 1.00) in DMF (12 mL) were stirred at RT for 1 h and the mixture was diluted with EtOAc. The mixture was washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 3-(dibenzylamino)-3H-spiro[benzo[b][1,4]oxazepine-2,1′-cyclohexan]-4 (5H)-one as an off-white solid (0.387 g, 64%). MS m/z 427.1 (MH+)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16](=[O:19])[CH:17]=O)[CH3:14].[CH:20]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1>>[CH2:13]([O:15][C:16]([CH:17]1[NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][C:6]=2[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:20]12)=[O:19])[CH3:14]
Reactant: C1=CCCCCCC1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C=O
Product: CCOC(=O)C1Nc2ccc(OC(F)(F)F)cc2C2CCCCCCC12

Procedure:
Compound 76 was prepared from 4-(trifluoromethoxy)-aniline, glyoxylic acid ethyl ester and cyclooctene by the automated process.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12](=[O:27])[C@H:13]([CH:24]([CH3:26])[CH3:25])[NH:14][C:15]([O:17]C1C=CC=CC=1)=O.N#N>O1CCOCC1>[CH3:10][O:11][C:12](=[O:27])[C@@H:13]([NH:14][C:15]([N:2]([CH3:1])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:17])[CH:24]([CH3:25])[CH3:26]
Reactant: CNCc1ccccn1
Reactant: COC(=O)[C@@H](NC(=O)Oc1ccccc1)C(C)C
Agent: N#N
Solvent: C1COCCO1
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1ccccn1)C(C)C
Yield: 92.5 %

Procedure:
A solution of 2.68 g (22.0 mmol) of 2-(methylaminomethyl)-pyridine, from step 3a above, and 5.02g (20.0 mmol) of phenoxycarbonyl-L-valine methyl ester, from step 3b above, in 20 mL of 1,4-dioxane was purged with N2. The solution was then heated at reflux for four hours under a N2 atmosphere, then the solution was concentrated in vacuo. The resulting residue was dissolved in ethyl ether and extracted into 1N HCl. The aqueous layer was adjusted to about pH 9 with solid sodium carbonate and extracted twice with methylene chloride. The organic layers were combined and washed with 0.2M phosphate buffer at pH 7.0. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo, affording 5.17 g of the title product as a light yellow oil. NMR (CDCl3)δ0.95 (dd,3H), 2.19 (m, 1H), 3.03 (s,3H), 3.72 (s,3H), 4.42 (dd, 1H), 4.54 (s,2 H), 6.14 (bs,1H), 7.26 (m,2H), 7.70 (dt,1H), 8.56 (m, 1H) .
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+].[CH3:39]O>>[N:33]([CH2:13][C@@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:24])[CH3:23])[OH:12])=[N+:34]=[N-:35].[CH:28]([O:27][CH:4]([CH3:3])[CH3:5])([CH3:29])[CH3:39]
Reactant: [N-]=[N+]=[N-]
Reactant: CO
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: CC(C)OC(C)C
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN=[N+]=[N-])C(C)C)ccc1OC

Procedure:
The solution of 3.10 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (Example 1b) in 64 ml of methanol is admixed with 1.04 g of sodium azide and 0.62 g of ammonium chloride and stirred at reflux over 6 hours. The reaction solution is cooled, poured onto ice-water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) and subsequent crystallization (diisopropyl ether) as white crystals. Rf=0.29 (1:2 EtOAc-heptane); Rt=21.60 (gradient II). m.p. 98-99° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=2[F:25])=[C:12]([CH3:17])[CH:11]=1)(=[O:9])=[O:8]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1cc(S(=O)(=O)NCCCCO)ccc1Br
Product: Cc1cc(S(=O)(=O)NCCCCO)ccc1-c1ccc(F)cc1F

Procedure:
Using a method analogous to that described in Example 40, 4-bromo-3-methylphenyl-sulfonic acid-(4-hydroxybutyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a thick oil. δC (DMSO, 62.9 MHz): 20.0, 26.4, 29.5, 43.1, 62.2, 104.2 (t, 25.4), 111.6 (d, J 21.5), 123.8 (d J 11.7), 124.4, 128.4, 131.7, 131.8 (m), 138.4, 139.4 (d, J 3.9), 159.4 (d J 250.0, 11.7) and 162.8 (dd 250.0, J 11.7).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCCCN
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3C)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxypropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (quin, J=6.63 Hz, 2H) 2.44 (s, 3H) 3.25 (s, 3H) 3.34 (q, J=6.65 Hz, 2H) 3.40 (t, J=6.19 Hz, 2H) 7.67 (d, J=7.83 Hz, 1H) 7.74 (s, 1H) 7.78 (d, J=6.82 Hz, 1H) 8.18 (br. s., 1H) 8.41 (d, J=6.06 Hz, 2H) 8.71 (t, J=5.31 Hz, 1H) 8.83-9.01 (m, 1H) 13.19 (br. s., 1H). MS m/z [M+H]+ 392.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=NO)[CH2:9][CH2:8]2)(=O)[CH2:2][CH3:3].[NH3:17].C[OH:19]>[Ni]>[NH2:17][CH:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:19])[CH2:9][CH2:8]2)[CH2:2][CH3:3]
Reactant: CO
Reactant: N
Reactant: CCC(=O)c1ccc2c(c1)CCC(=NO)N2
Agent: [Ni]
Product: CCC(N)c1ccc2c(c1)CCC(=O)N2
Reaction time: 12 h

Procedure:
Example P-12:9.2 g of 6-propionyl-3,4-dihydro-quinolin-2-one-oxime, 10 g ofdry ammonia and 3 g of Raney nickel in 130 ml of absolute methanol are placed in a hydrogenation autoclave. The batch is hydrogenated for 12 hours at a temperature of 50° C. and a pressure of 70 bar. The catalyst is then filtered off and the solvent, as well as the excess NH3, is removed under a water-jet vacuum. Purification is carried outby flash chromatography (eluant: ethanol/ether 1:3), yielding 8.2 g of 6-(1-aminopropyl)-3,4-dihydro-quinolin-2-one.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11](Cl)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2].[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH2:1]([O:3][C:4]1[C:9]2[N:10]=[C:11]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:12]=[C:13]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C:8]=2[N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CCOc1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 2 from 8-ethoxy-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 153°-155° C.) and piperazine. M.p.: 168°-170° C.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:38]=[CH:37][CH:36]=[CH:35][C:16]=1[O:17][CH2:18][CH:19]([OH:34])[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1)=O.Cl>C(O)C>[NH2:4][C:3]1[N:5]=[C:13]([C:15]2[CH:38]=[CH:37][CH:36]=[CH:35][C:16]=2[O:17][CH2:18][CH:19]([OH:34])[CH2:20][N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=3)[CH2:25][CH2:26]2)[CH:12]=[CH:11][N:2]=1
Reactant: N=C(N)N
Reactant: CN(C)C=CC(=O)c1ccccc1OCC(O)CN1CCN(c2ccc(Cl)cc2)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Nc1nccc(-c2ccccc2OCC(O)CN2CCN(c3ccc(Cl)cc3)CC2)n1

Procedure:
2.0 g (0.021 mole) of guanidine hydrochloride and 0.042 mole of a 30% strength sodium methylate solution are added to 10.0 g (0.021 mole) of 1-[2-(3-dimethylamino-1-oxo-propenyl)-phenoxy]-3-[4-(4-chlorophenyl)-piperazin-1-yl]-propan-2-ol.HCl in 250 ml of ethanol, and the mixture is refluxed for 12 hours. The hot solution is filtered and the filtrate is concentrated. The crude product is recrystallized from ethanol, and 3.5 g (38%) of product of melting point 159°-160° C. are isolated.
Reaction SMILES: C[O:2][C:3](=[O:33])/[CH:4]=[C:5](\[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][CH2:29][CH3:30])[C:12]=1[CH2:31][CH3:32])/[C:6]([O:8]C)=[O:7].[OH-].[Na+].CO.Cl>C(Cl)(Cl)Cl>[CH2:31]([C:12]1[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=[CH:16][C:11]=1[O:10]/[C:5](=[CH:4]\[C:3]([OH:33])=[O:2])/[C:6]([OH:8])=[O:7])[CH3:32]
Reactant: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)OC)C(=O)OC)c1CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1ccccc1OCCCOc1cccc(O/C(=C\C(=O)O)C(=O)O)c1CC

Procedure:
A solution of 42.0 parts of dimethyl 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxyfumaric acid and 7.36 parts of sodium hydroxide in 50% v/v aqueous methanol was refluxed for four hours. The reaction mixture was cooled, acidified with excess 2N hydrochloric acid and extracted with chloroform. Evaporation of the chloroform and trituration of the residue with 40/60 light petroleum ether gave an oily solid. This solid was dissolved in hot chloroform and addition of 40/60 light petroleum ether to the solution gave 33.8 parts of 2-ethyl-3-(3-[2-propylphenoxy]propoxy)phenoxyfumaric acid, m.pt. 104°-105°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].Br[CH2:18][CH:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][CH2:18][CH:19]([CH3:21])[CH3:20])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)CBr
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(C)C)c2c(c1)OC(C)(C)C2
Temperature: 85 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (167 mg, 0.75 mmol) in DMF (3 mL) was added 1-bromo-2-methylpropane (0.090 mL, 0.83 mmol) and cesium carbonate (520 mg, 1.6 mmol). The reaction mixture was stirred at 85° C. for 2 hr and cooled to room temperature. The mixture was quenched with H2O (10 mL), extracted with EtOAc (2×10 mL), dried over MgSO4 and concentrated. The residue was purified by flash column chromatography eluting with 5% EtOAc in hexanes to give colorless oil (193 mg, 92% yield). 1H NMR (400 MHz, CDCl3) δ 7.09 (s, 1 H) 7.05 (s, 1 H) 3.89 (s, 3 H) 3.80 (d, J=6.57 Hz, 2 H) 2.99 (s, 2 H) 2.02-2.16 (m, 1 H) 1.49 (s, 6 H) 1.04 (s, 3 H) 1.02 (s, 3 H); LCMS for C16H22O4 m/z 279.10 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14].[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[CH3:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14]
Reactant: Cc1ccncc1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(Br)cccc12
Product: Cc1ccncc1-c1cccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 64 %

Procedure:
Using Method A, 4-amino-8-bromo-N-cyclopropyl-cinnoline-3-carboxamide (143 mg, 0.47 mmol) and 4-methylpyridine-3-boronic acid (128 mg, 0.94 mmol) were reacted. After purification the title compound (96 mg, 64% yield) was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.53 (d, J=5.0 Hz, 1H), 8.50 (bm, 1H), 8.47 (s, 1H), 7.95 (a d, J=8.3 Hz, 1H), 7.77 (t, J=7.7 Hz, 1H), 7.69 (apparent d, J=7.0 Hz, 1H), 2.96 (m, 1H), 2.10(s, 3H), 0.88 (m, 2H), 0.62 (m, 2H). MS APCI, m/z=320, HPLC 1.55 min.
Reaction SMILES: [C:1]([N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:14][CH2:15][C:16]1[CH:27]=[CH:26][C:19]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1>C(#N)C>[Br-:14].[C:1]([N+:9]1[CH:13]=[CH:12][N:11]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]=[CH:21][C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)n1ccnc1
Reactant: COC(=O)C=Cc1ccc(CBr)cc1
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(Cn2cc[n+](C(=O)c3ccccc3)c2)cc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
To 5 ml of dry acetonitrile were added 1.7 g of 1-benzoylimidazole and 2.6 g of methyl 4-bromomethylcinnamate, and the mixture was stirred for 5 hours at room temperature. The precipitated crystals were collected by filtration and recrystallized from acetonitrile/diethyl ether to yield 3.5 g of 1-benzoyl-3-[4-(2-methoxycarbonylvinyl)benzyl]imidazolium bromide.
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.[C:34](=[O:47])([O:38][C:39]1[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=1)[O:35][CH2:36][CH3:37]>>[C:34](=[O:47])([O:38][C:39]1[CH:44]=[CH:43][C:42](/[CH:45]=[C:12](/[C:10]2[CH:9]=[CH:8][C:6]3[S:7][C:3]([CH3:2])([CH3:33])[S:4][C:5]=3[CH:11]=2)\[CH3:13])=[CH:41][CH:40]=1)[O:35][CH2:36][CH3:37]
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Oc1ccc(C=O)cc1
Agent: [Br-]
Product: CCOC(=O)Oc1ccc(/C=C(\C)c2ccc3c(c2)SC(C)(C)S3)cc1

Procedure:
In analogy to Example 45, by reacting [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide with ethyl 4- formylphenyl carbonate, there was obtained ethyl p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5-yl)propenyl]phenyl carbonate, melting point 93°-94° C. Hydrolysis of this compound with aqueous potassium hydroxide in ethanol gave p-[(E)-2-(2,2-dimethyl-1,3-benzodithiol-5yl)propenyl]phenol, melting point 123°-124° C.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[OH-].[Na+].Cl>O>[CH:5]([C:4]1([CH3:8])[NH:9][C:10]([C:12]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:2][C:1]1=[O:3])([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1nc2ccccc2cc1C(=O)O)C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C1(C)NC(c2nc3ccccc3cc2C(=O)O)=NC1=O

Procedure:
A solution of 2-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-3-quinolinecarboxylic acid (0.152 mol), in water (50 mL) containing sodium hydroxide (0.06 mol) is heated at 75° to 80° C. for two hours. The solution is cooled in an ice bath and acidified with concentrated hydrochloric acid, added in small increments. The resulting precipitate is filtered, washed with water, air dried, and recrystallized from acetone to afford the 2-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid, mp 239°-243.5° C.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]([OH:11])=O)[N:5]=[N:4][N:3]=1.Cl.[CH3:13][O:14][NH2:15].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:13][O:14][NH:15][C:9](=[O:11])[CH2:8][CH2:7][N:6]1[C:2]([SH:1])=[N:3][N:4]=[N:5]1
Reactant: O=C(O)CCn1nnnc1S
Reactant: CON
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CONC(=O)CCn1nnnc1S
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
To an ice cold and stirred solution of 5-mercapto-1H-tetrazole-1-propionic acid (1.04 g) in N,N-dimethylformamide (60 ml) is added N,N'-carbonyldiimidazole (1.16 g). After stirring for 15 minutes at 0° C., the mixture is mixed with a solution of methoxyamine hydrochloride (600 mg) and triethylamine (720 mg) in N,N-dimethylformamide (6 ml) and stirred for 1 hour at 0° C. The reaction mixture is poured into diluted hydrochloric acid and extracted with a mixture of ethyl acetate and methyl ethyl ketone (2:1). The solvent is evaporated from the extract to leave crystalline 5-mercapto-1H-tetrazole-1-propionohydroxamic acid methyl ester (1.2 g). mp. 170°-171° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][N:12]=1.C(N(CC)CC)C>CN(C=O)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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1nccc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nccc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.0 g (4.0 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 513 mg (4.3 mmol) 2-amino-5-ethynyl-pyridine using 75 mg (0.40 mmol) CuI, 276 mg (0.40 mmol) PdCl2(PPh3)2 and 5.4 mL (39.5 mmol) triethylamine in 40 mL dry DMF. After completion of the reaction the solvent is removed under vacuum and the product is purified by chromatography on silica gel using a DCM/MeOH gradient (100:0 to 90:10). Yield: 617 mg (64%).