Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)=O)C.[CH2:17]1[CH:19]([C:20]([NH2:22])=[NH:21])[CH2:18]1.Cl.CC(C)([O-])C.[K+]>CO>[CH:19]1([C:20]2[N:22]=[C:4]([OH:16])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[N:21]=2)[CH2:17][CH2:18]1
Reactant: N=C(N)C1CC1
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Oc1cc(-c2ccc(Cl)c(Cl)c2)nc(C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
To a solution consisting of 3-(3,4-dichlorophenyl)-3-oxo-propionic acid ethyl ester (252 mg, 0.967 mmol) and MeOH were added cyclopropylcarbamidine hydrochloride (140 mg, 1.16 mmol) and potassium tert-butoxide (266 mg, 2.37 mmol). The reaction mixture was stirred at rt overnight, then concentrated. Water and CH2Cl2 were added, and the mixture was adjusted to pH 7 with glacial acetic acid. The layers were separated, and the aqueous phase was extracted with EtOAc. The organics were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound as a white solid (133 mg, 49%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:19][CH3:20])[N:12]2[CH2:15][CH2:16][CH2:17]Cl)=[C:8]([NH2:21])[N:7]=1)[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[N:31]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(#N)C>[NH2:21][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[N:10]=[C:11]([O:19][CH3:20])[N:12]2[CH2:15][CH2:16][CH2:17][N:34]1[CH2:35][CH2:36][N:31]([CH2:37][CH2:38][OH:39])[CH2:32][CH2:33]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Reactant: OCCN1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2nc(OC)n(CCCN3CCN(CCO)CC3)c2n1
Temperature: 70 °C

Procedure:
2-(Butyloxy)-9-(3-chloropropyl)-8-(methyloxy)-9H-purin-6-amine (for example, as prepared for Intermediate 39) (80 mg, 0.255 mmol), DIPEA (0.134 mL, 0.765 mmol) and 2-(1-piperazinyl)ethanol (commercially available, for example, from Aldrich) (133 mg, 1.020 mmol) was heated in acetonitrile (2 mL) in a test-tube in a Radley greenhouse. The reaction was heated at 70° C. for 28 hours then allowed to cool and evaporated in vacuo. Aqueous sodium bicarbonate was added and the mixture was extracted several times with chloroform, the chloroform being filtered through a hydrophobic frit separator. The solvent was removed to give a brown gum (171 mg) which was purified on MDAP (method A). The fractions were evaporated in vacuo and the residue worked up with an aqueous sodium bicarbonate/chloroform extraction as before and the solvent removed to give the title compound as a colourless oil (80 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17].Cl>CN(C=O)C>[CH2:17]([S:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH:16]=[CH2:15]
Reactant: Oc1ccc(S)cc1
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCSc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 101.3 %

Procedure:
To a stirred solution of 4-hydroxythiophenol (1.6) (4.30 g, 34.1 mmol) in DMF (25 mL) were added K2CO3 (4.71 g, 34.1 mmol) and allyl bromide (3.09 mL, 34.1 mmol) at ice-water temperature, and the mixture was stirred for 15 minutes, prior to stirring overnight at room temperature. After the addition of 1 M aqueous HCl, the mixture was extracted with ether (3×). The combined organic layer was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/10 to 1/6) to give 1.7 (5.74 g, 70%) as a white semi-solid. The 1H and 13C NMR spectra and mass spectrum were identical to the reported values (Tetrahedron 1994, 50, 10321-10330).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][C:4]=1[N+:12]([O-])=O)#[N:2].C(O)(=O)C>[Fe]>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[S:7][C:3]=1[C:1]#[N:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C#N)s1
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)c(C#N)s1
Yield: 69.1 %

Procedure:
A suspension of methyl 5-cyano-4-nitro-thiophene-2-carboxylate (0.17 mol, 36 g) and iron powder (0.51 mol, 28.5 g) in glacial acetic acid 68 mL (1.2 mol) was refluxed for 3 hours. The crude was concentrated under vacuum and neutralized with diluted ammonia. The aqueous layer was extracted with ethyl acetate (3×250 mL) and dried over Na2SO4. The filtrate was evaporated to dryness to give a yellow solid, which was purified by flash chromatography over silica gel using hexane/ethyl acetate (38:12) as eluent, to afford the title compound as a yellow solid (21.4 g, 69%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH2:3][O:4][NH2:5].[N+:13]([C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]>C(Cl)(Cl)Cl>[N+:13]([C:16]1[CH:17]=[C:18]([NH:22][C:23]([NH:5][O:4][CH2:3][CH:2]([OH:1])[CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: NOCC(O)CN1CCCCC1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: ClC(Cl)Cl
Product: O=C(NOCC(O)CN1CCCCC1)Nc1cccc([N+](=O)[O-])c1

Procedure:
O-(2-hydroxy-3-piperidino-propyl)-hydroxylamine (1,74 g, 0,01 mol) was dissolved in 25 ml abs. chloroform and 1,64 g (0,01 mol) 3-nitrophenyl isocyanate in 20 ml abs. chloroform was added thereto while stirring. After 1 hour reaction the mixture was evaporated and purified by column chromatography. The oil thus obtained was crystallized from diethyl ether. Yield: 1,84 g (54%). Mp.: 137-139° C.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([Br:19])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[C:23]([I:30])[CH:22]=1>>[Br:19][C:13]1[C:12]2[C:11]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([Cl:20])=[CH:22][C:23]=3[I:30])=[C:10]3[CH:6]([CH2:2][C:3]([OH:5])=[O:4])[CH2:7][CH2:8][N:9]3[C:17]=2[CH:16]=[C:15]([F:18])[CH:14]=1
Reactant: CC(C(=O)[O-])C1CCn2c1cc1c(Br)cc(F)cc12
Reactant: O=C(Cl)c1ccc(Cl)cc1I
Product: O=C(O)CC1CCn2c1c(C(=O)c1ccc(Cl)cc1I)c1c(Br)cc(F)cc12

Procedure:
Starting from (+/−)-methyl(8-bromo-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (example 7, Step 8) and 4-chloro-2-iodobenzoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8].[N+:19]([C:22]1[CH:31]=[C:30]([C:32]([NH:34][NH2:35])=[O:33])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])([O-:21])=[O:20].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:35][NH:34][C:32]([C:30]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([N+:19]([O-:21])=[O:20])[CH:31]=3)=[O:33])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Reactant: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(Cl)c(Cl)c3)c2O)cc1[N+](=O)[O-]
Yield: 87.8 %

Procedure:
From 1-[5-(3,4-dichlorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.70 mmol, 200 mg) synthesized in Synthetic Example 1, methyl 2-nitro-4-hydrazinocarbonylbenzoate (0.70 mmol, 167.8 mg) of Reference Synthetic Example 40 and tosylic acid monohydrate (36.2 mg, 0.21 mmol), 311.1 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 88%).
Reaction SMILES: [Cl-].[Li+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C1CCN2C(=NCCC2)CC1.[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31][CH:32]=O>CC#N>[F:28][C:29]([F:35])([F:34])[CH2:30][CH2:31]/[CH:32]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=CCCC(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)/C=C/CCC(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a suspension of lithium chloride (0.504 g, 11.9 mmol) in MeCN (20 mL) were added ethyl 2-(diethoxyphosphoryl)acetate (available from Aldrich) (1.91 mL, 9.52 mmol) and DBU (1.42 mL, 9.52 mmol) at room temperature. The mixture was cooled to 0° C., and 4,4,4-trifluorobutanal (available from Matrix Scientific) (1.00 g, 7.93 mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with additional EtOAc. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated. The residue was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford (E)-ethyl 6,6,6-trifluorohex-2-enoate 68.B (6:1 E/Z) as a colorless liquid (1.13 g, 73%).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][S:7][CH2:8][CH2:9]O)[C:3]([OH:5])=[O:4].[ClH:11]>>[ClH:11].[NH2:1][CH:2]([CH2:6][S:7][CH2:8][CH2:9][Cl:11])[C:3]([OH:5])=[O:4]
Reactant: NC(CSCCO)C(=O)O
Agent: Cl
Product: NC(CSCCCl)C(=O)O
Reaction time: 7 h
Yield: 75.4 %

Procedure:
33.9 g of 2-amino-3-(2-hydroxy-ethylsulfanyl)-propionic acid was dissolved in 800 mL of concentrated hydrogen chloride and the solution was stirred for 7 h to obtain a buff solid. The solid was recrystallized in isopropanol to obtain a white powder (34.2 g). Yield 75.4%, mp 185-186° C.
Reaction SMILES: N12CCCN=C1CCCCC2.[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:37][CH2:38][CH2:39]Br)=[C:28]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19].[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:37][CH2:38][CH2:39][N:51]4[CH2:50][CH2:49][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:53][CH2:52]4)=[C:28]([O:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1ccc(Nc2ncnc3cc(OCCBr)c(OC4CCCC4)cc23)cc1Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cc3ncnc(Nc4ccc(F)c(Cl)c4)c3cc2OC2CCCC2)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
340 mg of 1,8-diazabicyclo[5.4.0]undec-7-ene are added at ambient temperature to 940 mg of 4-[(3-chloro-4-fluorophenyl)amino]-6-cyclopentyloxy-7-(2-bromoethoxy)-quinazoline and 1.00 g of N-(tert.butyloxycarbonyl)-piperazine in 30 ml of acetonitrile. The reaction mixture is heated to 60° C. for five hours. Then a further 0.2 g of N-(tert.butyloxycarbonyl)-piperazine and some 1,8-diazabicyclo[5.4.0]undec-7-ene are added. The yellow reaction solution is stirred for two hours at 60° C. and then overnight at ambient temperature, during which time a white precipitate is formed. This is suction filtered, washed with a little acetonitrile and dried. 453 mg of the desired product are obtained as a white solid. The mother liquor is concentrated by evaporation and the flask residue is chromatographed over a silica gel column with methylene chloride/methanol (95:5). Another 300 mg of the desired product are obtained.
Reaction SMILES: O.[F:2][C:3]1[C:23]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:22][C:6]([O:7][C:8]2[C:9]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[C:5]([N+:37]([O-])=O)[CH:4]=1>C(O)(=O)C.[Fe]>[NH2:37][C:5]1[CH:4]=[C:3]([F:2])[C:23]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:22][C:6]=1[O:7][C:8]1[C:9]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1nc(OC)ccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 35 °C
Reaction time: 2 h

Procedure:
To a mixture of an iron powder, acetic acid and water is added a solution of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine in acetic acid dropwise while maintaining the temperature of the reaction solution at 35° C. or lower. After completion of the addition, the mixture is stirred for 2 hours, then, the reaction solution is filtrated through Celite, and diluted with ethyl acetate. The mixture is neutralized with saturated aqueous sodium bicarbonate solution, the organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated, then, the resulted residue is subjected to silica gel chromatography to obtain 3-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O)[CH3:21].[O-]CC.[Na+]>>[CH2:20]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[CH:30][C:27]=1/[CH:28]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCOCCOc1c(C=O)cccc1OC
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: CC[O-]
Agent: [Na+]
Product: CCOCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(C#N)cc2)cccc1OC
Yield: 39 %

Procedure:
The title compound was prepared by condensation of Intermediate 4 (335 mg, 1.252 mmol) with 2-(2-ethoxyethoxy)-3-methoxy-benzaldehyde (339 mg, 1.753 mmol) in presence of sodium ethoxide (170 mg, 2.506 mmol) according to the procedure described in Example 9 to yield 231 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.16 (t, J=6.6 Hz, 3H), 3.45-3.52 (m, 4H), 3.78 (s, 3H), 4.00-4.08 (m, 2H), 6.78 (d, J=15.6 Hz, 1H), 6.94-7.01 (m, 3H), 7.50-7.58 (m, 3H), 7.92 (d, J=7.8 Hz, 2H), 8.02 (d, J=4.8 Hz, 1H), 8.20 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 474.45 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][C:4]=1[Cl:22].[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:22][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[CH2:2][N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])[O:10][CH:9]([C:13]([F:16])([F:15])[F:14])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: CNC(C)C
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(CN(C)C(C)C)cc2OC1C(F)(F)F
Reaction time: 3 h

Procedure:
The ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (01597/1 PR) (1.0 g, 2.5 mmol) was dissolved in DMF (5 mL). The solution was cooled at ice bath under nitrogen and the isopropyl(methyl)-amine (0.26 mL, 2.5 mmole) was added into the solution followed by addition of potassium carbonate (0.345 g, 2.5 mmol). After the mixture was stirred at r.t for 3 hr, LCMS indicated that the product was formed. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4 and filtered. The filtrate was concentrated to afford the crude product. The ester was of suitable purity to use without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:6]([N:7]2[C:11](=[O:12])[C:10]3=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]3[C:8]2=[O:17])[CH2:5][O:4][N:3]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>O1CCCC1>[Cl:1][C:2]1[CH:6]([NH:7][C:11](=[O:12])[C:10]2[C:9](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([CH3:18])=[CH:20][CH:21]=2)=[O:17])[CH2:5][O:4][N:3]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C1c2ccccc2C(=O)N1C1CON=C1Cl
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)c2ccccc2C(=O)NC2CON=C2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Chloro-4-phthalimido-4,5-dihydroisoxazole (4 g, 16 mmol) was dissolved in 50 ml of dried tetrahydrofuran. 4-Methylbenzylamine (2.18 g, 18 mmol) was added at room temperature and the reaction solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo, and the residue recrystallized from chloroform to give 4.8 (80.7%) of the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7](Cl)=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2].[SH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: Sc1ccncc1
Reactant: CC(=O)Nc1nc(CO)c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CO)c(Sc2ccncc2)s1
Temperature: 110 °C
Yield: 66.1 %

Procedure:
A mixture of 2-acetylamino-5-chloro-4-hydroxymethylthiazole (1 g), 4-mercaptopyridine (0.6 g) and potassium carbonate (1 g) in N,N-dimethylformamide (20 ml) was heated at 110° C. for 8 hours with stirring. The reaction mixture was poured into ice water and filtered by suction. The filtrate was extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1) and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 75 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-acetylamino-4-hydroxymethyl-5-(4-pyridylthio)thiazole (0.90 g, yield: 64.3%). mp: 220°-222° C. (dec.)
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[C:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CCCCCC.O1CCCC1>[CH2:17]([C:16]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:23][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCC(=O)c1ccccc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6 M n-butyl lithium in hexane, 25 mmol of heptanophenone and 70 mL of tetrahydrofuran. Upon concentrating the reaction, a solid precipitated out which was triturated with ether and filtered (m.p. 119-120.5° C.). 1H NMR (CDCl3) δ 0.84 (t, 3 H), 1.1-1.4 (m, 8 H), 1.9-2.0 (m, 2 H), 2.89 (d, 1 H), 2.93 (d, 1 H), 3.24 (d, 1 H), 3.35 (d, 1 H), 7.2-7.5 (m, 5 H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:15]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][CH:7]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21].Cl>C(Cl)Cl>[Br:16][C:17]1[CH:18]=[C:19]([C:20]([C:8]2[C:9]3[C:15]([CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]([CH3:5])[CH:7]=2)=[O:21])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Cc1ccc2cccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C(=O)c2cccc(Br)c2)c2cccccc1-2
Reaction time: 0.25 h

Procedure:
Aluminum chloride (1.87 g) was added to a solution of 1-methylazulene (2 g) in methylene chloride (20 ml) at 0° C. and the mixture was stirred for 15 minutes. Then, a solution of 3-bromobenzoyl chloride (1.86 ml) in methylene chloride (5 ml) was added dropwise to the reaction mixture at 0° C. and the mixture was stirred for one hour. The reaction mixture was added to 10% aqueous solution of hydrochloric acid under cooling with ice and was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (3-bromophenyl)(3-methylazulen-1-yl)methanone (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]([CH:20]([CH3:24])[C:21]([OH:23])=O)[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:12][N:11]([CH:20]([CH3:24])[C:21]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:23])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OCC(F)(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
214 mg (purity 73%, 0.39 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxo-5-(2,2,2-trifluoroethoxy)pyridin-1(2H)-yl]propanoic acid (racemate) and 83 mg (0.43 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 113 mg (purity 70%, 35% of theory)
Reaction SMILES: O[CH:2]1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[N:5]([CH2:17][C:18]#[CH:19])[C:4]([CH3:21])([CH3:20])[CH2:3]1.C(O)=[O:23]>>[CH3:20][C:4]1([CH3:21])[N:5]2[N:6]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH:2]([CH2:19][C:18](=[O:23])[CH2:17]2)[CH2:3]1
Reactant: O=CO
Reactant: C#CCN1N(C(=O)OCc2ccccc2)C(O)CC1(C)C
Product: CC1(C)CC2CC(=O)CN1N2C(=O)OCc1ccccc1
Yield: 18 %

Procedure:
A stirred solution of 105 (2.5 g, 8.6 mmol) in formic acid (10 mL) was heated at 100° C. for 5 h. After complete consumption of 105 (as monitored by TLC), formic acid was evaporated under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with saturated with NaHCO3 solution (2×50 mL), water (50 mL) and brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound which was purified through preparative HPLC to afford 106 (0.52 g, 18%). 1H NMR (CDCl3) δ 7.30-7.40 (m, 5H), 5.25 (s, 2H), 3.62 (m, 1H), 2.76 (m, 1H), 2.42 (m, 1H), 2.20 (m, 1H), 2.09 (s, 1H), 1.65 (m, 1H), 1.22 (s, 3H), 1.13 (s, 3H).