Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2].[OH:35][C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([OH:24])[CH2:19][CH2:20][N:21]([C:37](=[O:38])[C:36]([OH:35])([CH3:41])[CH3:40])[CH2:22][CH2:23]4)[N:14]3[CH3:17])=[C:10]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCNCC3)n(C)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(O)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.2 %

Procedure:
To a mixture of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]piperidin-4-ol (150 mg, 0.32 mmol), 2-hydroxyisobutyric acid (41 mg, 0.39 mmol) and DIPEA (68 μL, 0.39 mmol) in DCM (2 mL) was added HATU (149 mg, 0.39 mmol). The resulting mixture was allowed to stir at r.t. for 18 h then diluted with DCM and washed with sat. aq. NaHCO3. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-20%) affording 790 (60 mg, 34%). LCMS (method I): RT 3.09 min, [M+H]+ 549.3. 1H NMR (DMSO, 400 MHz): δ 8.02-8.01 (1 H, m), 7.64-7.63 (1 H, m), 7.27-7.23 (2 H, m), 5.84 (1 H, s), 5.42 (1 H, s), 4.25 (6 H, brd s), 3.98 (3 H, s), 3.77 (4 H, t, J=4.55 Hz), 3.60 (1 H, brd s), 3.2-3.24 (3 H, m), 2.11-2.10 (2 H, m), 2.06-1.94 (2 H, m), 1.38-1.30 (9 H, m)
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])[C:4]=1[O:14][CH3:15].[C-:16]#[N:17].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:15][O:14][C:4]1[C:5]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:16]#[N:17]
Reactant: COCCOc1cccc(CCl)c1OC
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1cccc(CC#N)c1OC
Temperature: 60 °C
Yield: 54.3 %

Procedure:
1-(Chloromethyl)-2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzene (0.33 g, 1.4 mmol) was dissolved in N,N-dimethylformamide (2 mL) followed by the addition potassium cyanide (0.12 g, 1.6 mmol), and the resulting mixture was heated at 60° C. for 18 hours. After cooling to room temperature, it was diluted with ethyl acetate (50 mL), washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (50% ethyl acetate/hexanes) to provide (2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.17 g, 0.76 mmol, 54% yield). 1H NMR (400 MHz, CDCl3): 7.03-7.00 (d, d, 1H), 6.95-6.89 (m, 2H), 4.16-4.14 (m, 2H), 3.94 (s, 3H), 3.79-3.77 (m, 2H), 3.70 (s, 2H), 3.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:20](=[O:21])[CH2:19][CH:18]([CH2:22][CH:23]=[O:24])[CH2:17][C:16]3=[O:25])[CH:9]=2)=[CH:4][CH:3]=1.[CH2:26](O)[CH2:27][CH2:28][OH:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH:15]3[C:16](=[O:25])[CH2:17][CH:18]([CH2:22][CH:23]4[O:29][CH2:28][CH2:27][CH2:26][O:24]4)[CH2:19][C:20]3=[O:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC=O)CC1=O
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)CC(CC2OCCCO2)CC1=O
Temperature: 80 °C
Reaction time: 0.75 h

Procedure:
To a solution of [4-(4′-chloro-4-methylbiphenyl-3-yl)-3,5-dioxocyclohexyl]-acetaldehyde (0.080 g, 0.23 mmol) and propane-1,3-diol (0.021 g, 0.27 mmol) in anhydrous toluene (4 ml) is added a single crystal of para-toluenesulfonic acid and the mixture is stirred at 80° C. for 45 minutes. After cooling to room temperature the solution is concentrated in vacuo to afford a crude product which is purified by flash column chromatography on silica (ethyl acetate eluant) to afford 2-(4′-chloro-4-methylbiphenyl-3-yl)-5-[1,3]dioxan-2-ylmethylcyclohexane-1,3-dione as a white foam.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([CH:7]=[CH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Solvent: CO
Product: C(=Cc1ccccc1)c1ccccc1
Reaction time: 11 h

Procedure:
Into a 30 mL two-neck flask, a methanol solution (0.04 g/L, 70 μL) of the [HPS-N(C2H4OC2H4OCH3)3Br]Pt particle complex prepared in Example 17 and 180 mg of trans-stilbene were charged and thereto, 2 mL of methanol was added. The inside of the system was purged with hydrogen and the reaction was effected at room temperature for 11 hours. A dibenzyl derived from reduction of trans-stilbene was obtained in a yield measured by G.C. of 93%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[S:13][C:12]([CH2:14][C:15]2[C:16](=[O:40])[N:17]([C@H:27]3[CH2:32][CH2:31][C@H:30]([O:33][CH2:34]C(OCC)=O)[CH2:29][CH2:28]3)[C:18]3[N:19]([N:24]=[CH:25][N:26]=3)[C:20]=2[CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=1)#[N:2].C[Mg]Br.[Cl-].[NH4+]>O1CCCC1>[OH:33][C:30]([CH3:31])([CH3:29])[CH2:34][O:33][C@H:30]1[CH2:29][CH2:28][C@H:27]([N:17]2[C:16](=[O:40])[C:15]([CH2:14][C:12]3[S:13][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][CH:11]=3)=[C:20]([CH2:21][CH2:22][CH3:23])[N:19]3[N:24]=[CH:25][N:26]=[C:18]23)[CH2:32][CH2:31]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ncnn12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)s2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Ethyl ({trans-4-[6-{[5-(2-cyanophenyl)thiophen-2-yl]methyl}-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl]cyclohexyl}oxy)acetate (0.25 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 0.44 mL) was added at room temperature. The reaction mixture was stirred at 70° C. for 6 hr, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.12 g, 49%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1.O>CN(C=O)C>[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N:16]([CH3:18])[CH3:17])[CH:11]=3)=[CH:4][C:3]=2[N+:20]([O-:22])=[O:21])=[CH:32][CH:31]=1
Reactant: CN(C)c1cccc(C(=O)Nc2ccc(Cl)c([N+](=O)[O-])c2)c1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cccc(C(=O)Nc2ccc(Sc3ccc(N)cc3)c([N+](=O)[O-])c2)c1
Temperature: 65 °C

Procedure:
To a solution of Example 239b (5.0 g, 15.6 mmol) in DMF (50 mL) was added K2CO3 (4.3 g, 17.0 mmol) and 4-aminothiophenol (1.9 g, 8.5 mmol). The mixture was heated at 65° C. for 16 h. The reaction was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with hexanes/ethyl acetate/methanol (50:40:10) to give the desired product (3.4 g, 53%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:6]([O:12][S:13](=[O:34])(=[O:33])[NH:14][C:15](=[O:32])[CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])=[C:5]([CH:35]([CH3:37])[CH3:36])[CH:4]=1)#[N:2].[H][H].Cl>N.C(OCC)C.[Ni]>[NH2:2][CH:1]=[C:3]1[CH:4]=[C:5]([CH:35]([CH3:36])[CH3:37])[C:6]([O:12][S:13](=[O:33])(=[O:34])[NH:14][C:15](=[O:32])[CH2:16][C:17]2[C:18]([CH:29]([CH3:30])[CH3:31])=[CH:19][C:20]([CH:26]([CH3:27])[CH3:28])=[CH:21][C:22]=2[CH:23]([CH3:25])[CH3:24])=[C:7]([CH:9]([CH3:11])[CH3:10])[CH2:8]1
Reactant: CC(C)c1cc(C(C)C)c(CC(=O)NS(=O)(=O)Oc2c(C(C)C)cc(C#N)cc2C(C)C)c(C(C)C)c1
Reactant: [H][H]
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCOCC
Product: CC(C)C1=CC(=CN)CC(C(C)C)=C1OS(=O)(=O)NC(=O)Cc1c(C(C)C)cc(C(C)C)cc1C(C)C

Procedure:
[(2,4,6-Triisopropyl-phenyl)-acetyl]-sulfamic acid 4-cyano-2,6-diisopropyl-phenyl ester (5.15 g, 9.8 mmol) was dissolved in 100 mL of methanolic ammonia and 2.0 g of Raney-nickel was added. The resulting mixture was stirred under 50 psi of hydrogen at room temperature for 20 hours. Filtered and concentrated the residue to give a dark solid. Suspended in diethyl ether and acidified with HCl gas. Concentrated in vacuo and neutralized the residue with saturated aqueous sodium bicarbonate. The resulting white suspension was used without further purification.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O-:14])(=O)[CH2:9][C:10]([O-:12])=[O:11].[Na]>CO>[C:10]([O:12][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:11])[CH2:9][C:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[O:14]
Reactant: OCc1ccco1
Reactant: O=C([O-])CC(=O)[O-]
Agent: [Na]
Solvent: CO
Product: O=C(CC(=O)OCc1ccco1)OCc1ccco1
Reaction time: 4 h

Procedure:
Furfuryl alcohol (196 parts, 2 moles) and 132 parts (1 mole) of ddimethyl malonate are mixed, and 0.5 -0.75 percent of sodium metal added. The mixture is heated to a temperature in the range from 101°-115° C. under a nitrogen atmosphere. Methanol is evolved and removed as the reaction progressed. After a period of four hours, a waxy solid is obtained. The liquid product obtained after washing with water is difurfuryl malonate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:6]([CH3:11])=[N:7][NH:8][C:9]=1[CH3:10].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([CH2:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[C:6]=1[CH3:11]
Reactant: O=Cc1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)n[nH]c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1c(C)nn(Cc2ccc(C=O)cc2)c1C

Procedure:
(3,5-Dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (1 g, 6.0 mmol), 4-(bromomethyl)-benzaldehyde (1.18 g, 6.0 mmol) and K2CO3 (1.73 g, 12.5 mmol) were refluxed in 5 ml acetonitrile for 12 h. After cooling, the mixture was filtered, and the solvent was removed under reduced pressure. The residue was purified by MPLC (silica gel, CH2Cl2/methanol 99:1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([OH:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:25](I)[CH3:26]>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:24][CH2:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCI
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)OCC
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (55% suspension in oil, 1.65 g) was added to a solution ethyl 3-(4-benzyloxyphenyl)lactate (10.30 g), which is the product of Reference example 1(b), in a mixture of N,N-dimethylacetamide (50 ml) and toluene (50 ml). The mixture was stirred at 40° C. for 30 minutes. To the reaction mixture were added ethyl iodide (3.3 ml) and toluene (5 ml). This mixture was stirred at 40° C. for 2 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=5/1 as the eluant to give the desired compound (5.50 g) as a syrup.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10].[C:18]([O-])([O-])=O.[K+].[K+].CI>O>[F:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([O:15][CH3:18])=[O:14])[CH:5]=[CH:6][C:7]=1[CH2:8][O:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: COCc1ccc(NC(C)(C)C(=O)O)cc1F
Agent: [K+]
Solvent: O
Solvent: CI
Product: COCc1ccc(NC(C)(C)C(=O)OC)cc1F
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The title compound was prepared according to General Method 5. A mixture of 2-(3-fluoro-4-(methoxymethyl)phenylamino)-2-methylpropanoic acid (1 g, 4.1 mmol), anhydrous K2CO3 (0.858 g, 6.2 mmol) and methyliodide (0.880 g, 6.2 mmol) was stirred at 60° C. for 3 h. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3), organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product that was purified by silica gel chromatography (eluant 30% ethyl acetate-hexane) to obtain methyl 2-(3-fluoro-4-(methoxymethyl)phenylamino)-2-methylpropanoate.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1.O.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:5]1[N:4]([CH2:11][CH2:12][OH:13])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Reactant: NCc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1NCc1ccccc1
Yield: 59 %

Procedure:
6.3 g (20 mmoles) 3,5-dibromo-1-(2'-hydroxyethyl)-4-nitropyrazole are heated in 20 ml benzylamine for 2 hours at 60° C. After cooling, the reaction mixture is poured on 50 ml of water, the separated product is filtered and recrystallized once from toluene/ligroine (1:1). 4 g (59 percent of theory) of 5-benzylamino-3-bromo-1-(2'-hydroxyethyl)-4-nitropyrazole are obtained in the form of yellow crystals with a melting point of 133° to 135° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12](O)(=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[OH-].[Na+]>>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:1][C:2]=2[CH:7]=1)[CH2:9][CH3:10]
Reactant: CCCc1ccc(O)c(N)c1
Reactant: O=C(O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccc2oc(-c3ccncc3)nc2c1
Temperature: 190 °C
Yield: 38.1 %

Procedure:
A mixture of 1.2 g of 2-amino-4-propylphenol, 0.98 g of isonicotinic acid and 32.8 g of polyphosphoric acid was stirred while heating at 190° C. for five hours. The mixture was cooled to room temperature and then poured into an ice-cooled aqueous solution of sodium hydroxide, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. Activated carbon was added thereto, which was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.72 g of 5-propyl-2-(pyridin-4-yl)-benzoxazole (hereinafter, referred to as “active compound 1”).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][F:11])=[CH:6][C:5]=1[NH:12]C(=O)C.S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][F:11])=[CH:6][C:5]=1[NH2:12]
Reactant: COC(=O)c1ccc(CF)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc(CF)cc1N
Yield: 101.6 %

Procedure:
To a solution of 2-acetylamino-4-fluoromethyl-benzoic acid methyl ester (1.5 g, 6.66 equiv) in MeOH (50 mL) was added concd sulfuric acid (4 mL) and the mixture was refluxed for 1 h. The mixture was cooled down and concentrated in vacuo. Water was added and the pH was adjusted to 9-10 by addition of 2N NaOH. The aqueous phase was extracted with AcOEt. The organic phase were combined, washed with brine and dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound as a yellow-orange oil (1.24 g, 100%) (ES-MS: m/z 184.1 [M+H]+, rt 4.91 min).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21]([NH2:23])=O)[NH:8]2)=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCCC1>[Cl:1][C:2]1[C:10]([N:11]([CH3:20])[S:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)(=[O:14])=[O:13])=[C:9]2[C:5]([CH:6]=[C:7]([C:21](=[S:33])[NH2:23])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CN(c1c(Cl)ccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Solvent: C1CCOC1
Product: CN(c1c(Cl)ccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 6-chloro-7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (0.70 g), Lawesson's reagent (0.77 g) and tetrahydrofuran (20 ml) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated, toluene was added, and the resulting crystals were filtrated, washed with toluene, and dried to give the title compound (0.60 g, yield 84%) as yellow crystals. melting point 200-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]#[N:25])[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccnc1Cl
Reactant: O=S(=O)(c1cccc(Cl)c1)C1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2cccc(Cl)c2)CC1
Yield: 66.2 %

Procedure:
Using the procedure from Example 7A, 4-[(3-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2-chloro-3-cyanopyridine (108 mg, 0.76 mmol), DIEA (0.2 ml, 1.14) and 1,4-dioxane (0.3 ml) to afford the title compound (91 mg), a yellow solid, in 62% yield.
Reaction SMILES: [C:1]([CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)([OH:3])=[O:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH3:20])=[C:12]1[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)([OH:3])=[O:2]
Reactant: [H][H]
Reactant: Cc1c(-n2ccnc2)n(CCCCCC=CC(=O)O)c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-n2ccnc2)n(CCCCCCCC(=O)O)c2ccccc12

Procedure:
1-(7-Carboxyhept-6-enyl)-2-(1-imidazolyl)-3-methylindole (20 mg) is dissolved in 1 ml of absolute ethanol with a catalytic amount of 10% palladium on charcoal and hydrogenated at 1 atmosphere pressure. After one mole of hydrogen is consumed the catalyst is removed by filtration and washed with a few milliliters of ethanol. The combined filtrates are concentrated to yield the 1-(7-carboxyheptyl)-3-methyl-2-(1-imidazolyl)indole.
Reaction SMILES: [NH:1]1[CH:8]=[C:7]([CH2:9][C:10]([O:12]CC)=[O:11])[C:5](=[O:6])[NH:4][C:2]1=S.ClCC(O)=[O:18].Cl>O>[NH:1]1[CH:8]=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[C:5](=[O:6])[NH:4][C:2]1=[O:18]
Reactant: O=C(O)CCl
Reactant: CCOC(=O)Cc1c[nH]c(=S)[nH]c1=O
Agent: Cl
Solvent: O
Product: O=C(O)Cc1c[nH]c(=O)[nH]c1=O

Procedure:
Ethyl (2-thiouracil-5-yl)acetate (33, 7.8 g, 36 mmol) was mixed with chloroacetic acid (1.9 g, 20 mmol) and water (47 ml) and refluxed for 2 hours. Concentrated hydrochloric acid (22 ml) was added and the reaction mixture was refluxed overnight. The reaction mixture was filtered and the precipitate was washed once with water and dried. The procedure was repeated with the precipitate in place of 8 yielding 4.19 g (68%) of the title compound as a white solid. 1H-NMR (DMSO-d6/TMS): 2=3.13 (s, 2H, CH2COO); 7.35 (d, 1H, J=6.5 Hz, H-6); 10.74 (m, 1H, H-1); 11.09 (s, 1H, H-3); 12.20 (br, 1H, COOH). 13C-NMR (DMSO-d6/TMS): δ=31.3 (CH2COO); 106.6 (C-5); 139.7 (C-6); 151.2 (C-2); 164.0 (C-4); 171.9 (COOH).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]>CO.O>[OH:1][CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(C)=O
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(C)O

Procedure:
The same procedure of Example 5 is repeated with the only differences that 1.95 g of ethyl 3-oxo-butyrate were weighed and dissolved in MeOH/H2O 19/1 (v/v) and the catalyst of Example 15 was utilized. At the end of the reaction, the ethyl 3-hydroxybutyrate resulted to be equal to 91%, while the ethyl 3-dimetoxybutyrate resulted equal to 9%. The stereoinduction was <99% in favour of the antipode (S).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[C@H:17]([NH:18][C:19](=O)[C:20]3[CH:34]=[CH:33][C:23]([C:24]([N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15][O:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][C:9]=1[O:10][CH3:11])[C:19]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1)=[N:18][C@H:17]1[C@@H:12]2[CH2:13][O:14][CH2:15][CH2:16]1)[CH3:2]
Reactant: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)C)cc1)=N[C@@H]1CCOC[C@H]21

Procedure:
5 mmol of N-[(3R,4R)-3-(3-Ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-N′,N′-diisopropyl-terephthalamide are heated to boiling under reflux for 4 h in 25 ml of acetonitrile and 15 mmol of phosphorus oxytrichloride. After distilling off the excess of phosphorus oxytrichloride and about 20 ml of acetonitrile, the residue is partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The solid residue is purified by column chromatography on SiO2 (di-isopropylether/methanol/triethyl amine 18/1/1 vol/vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid foam. M.p. 98-102° C. (unsharp, enamel-like shrinking starting at about 88° C.)
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4]CO.[C:8]([O:11][C:12](=O)C)(=[O:10])[CH3:9]>>[C:8]([O:11][CH2:12][CH:3]([N:2]([CH3:1])[CH3:7])[CH3:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)CCCO
Product: CC(=O)OCC(C)N(C)C

Procedure:
14.4 g of 3-dimethylamino-1-propanol and 14.3 g of acetic anhydride are reacted and worked up as described in Example 7. Yield: 14.9 g (73.1%) of analytically pure product (analysis by gas chromatography) with a boiling point of 53° C./12 torr.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1ccc(C)c(C)c1)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CC(=O)O)(Cc1ccc(C)c(C)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 11.6 g (29.5 mmol) tert-butyl 4-(3,4-dimethyl-phenyl)-3,3-bis-ethoxycarbonyl-butanoate and 100 mL DCM was combined with 20 mL TFA, the reaction mixture was stirred for 3 h at RT and evaporated down under reduced pressure.