Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C:12]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)([CH2:15][NH:16][CH3:17])[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1.CO>[ClH:24].[ClH:1].[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:12]2([CH2:15][NH:16][CH3:17])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:19][CH:20]=1
Reactant: CNCC1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNCC1(c2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 4M solution of hydrochloric acid in dioxane (10 ml) was added dropwise to a solution of 4-(4-chlorophenyl)-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester (142 mg, 0.42 mmol) in methanol (10 ml). The reaction was stirred overnight at room temperature. After this period of time, the solvents were concentrated to give [4-(4-chlorophenyl)-piperidin-4-ylmethyl]-methylamine bis-hydrochloride (132 mg, 0.42 mmol, 100%). This compound was used in the subsequent step without further purification. LC-MS (LCT2) m/z 239 [M+H+], Rt 0.53 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:35])[CH:32]([CH3:34])[CH3:33]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=3)[CH2:13][CH:12]([C:26]3[O:28][N:35]=[C:31]([CH:32]([CH3:34])[CH3:33])[N:30]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CC(c2cccc(C(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: CC(C)C(N)=NO
Product: CC(C)c1noc(C2CC(c3cccc(C(F)(F)F)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
75 mg (0.17 mmol) of the compound from Example 150A and 27 mg (0.25 mmol) of N′-hydroxy-2-methylpropanimidamide were reacted according to the General Method 2. Yield: 26 mg (33% of theory)
Reaction SMILES: COC(C1C(O)=C(O)N=C(CC2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)CCCC2)N=1)=O.[CH3:25][NH:26][C:27]([C:29]1[N:30]=[C:31]([CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][CH2:40][CH2:39]2)[NH:32][C:33](=[O:36])[C:34]=1[OH:35])=[O:28]>>[CH2:25]([NH:26][C:27]([C:29]1[C:34]([OH:35])=[C:33]([OH:36])[N:32]=[C:31]([CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:39][CH2:40][CH2:41][CH2:42]2)[N:30]=1)=[O:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNC(=O)c1nc(CC2(c3ccccc3)CCCC2)[nH]c(=O)c1O
Reactant: COC(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O
Product: O=C(NCc1ccccc1)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1O

Procedure:
5,6-Dihydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid benzylamide was synthesized as an off-white solid (20 mg, 30%) from 55 mg of 5,6-dihydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid methyl ester following the procedure described for 5-hydroxy-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid methylamide (Example 9). LCMS: m/z=403.8 (MH+).
Reaction SMILES: ON1C(=O)CCC1=O.O[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1)=[O:11].[SH:25][CH2:26][CH2:27][NH2:28].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C(O)C(N)(CO)CO.Cl>CN(C)C=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[C:10]([NH:28][CH2:27][CH2:26][SH:25])(=[O:11])[CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1
Reactant: NCCS
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CN(C)C=O
Product: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCS
Reaction time: 0.5 h

Procedure:
An aliquot (0.1 ml) of 44 mM biotin-N-hydroxysuccinimide (Zymed Laboratories, Inc., San Francisco, Calif.) in N,N-dimethylformamide was incubated with 1.0 ml of 4.4 mM 2-mercaptoethylamine in 0.1M sodium phosphate buffer, pH 7.0, containing 5 mM EDTA, at 30° C. for 30 minutes, and 0.1 ml of 1M Tris-HCl buffer, pH 7.0, was added.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].Br[C:15]1[CH:16]=[C:17]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)[CH:18]=[CH:19][CH:20]=1.CO>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]I>[O:22]1[CH:23]=[CH:24][O:25][CH:21]1[C:17]1[CH:16]=[C:15]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Brc1cccc(C2OCCO2)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1C(=O)N(c2cccc(C3OC=CO3)c2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Isatin (3.2 g, 0.0218 mol) was dissolved in anhydrous DMF (75 ml) and cooled in an ice-bath under a nitrogen atmosphere. To this cold solution, sodium hydride (0.575 g, 0.0239 mol) was added and the reaction was stirred at 0° C. for 1.5 hours. This solution was then treated with 2-(3-bromophenyl)-1,3-dioxolane (5 g, 1 equivalent) followed by CuI (8.3 g, 2 equivalents). The resulting suspension was heated in an oil-bath under nitrogen at 130-140° C. for 16 hours. It was then cooled to room temperature and diluted with an equal volume of chloroform. This suspension was filtered and the filtrate was concentrated under reduced pressure. A viscous brown oil was recovered which was suspended in xylenes (150 ml) wand evaporated to dryness. The residue was used as such for the next reaction. TLC (5% methanol in chloroform) showed clean conversion; Rf (product)=0.86.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-:23]#N.[K+]>C(O)C#C>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]#[CH:23])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reactant: [C-]#N
Agent: C#CCO
Agent: [K+]
Product: C#CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Reaction time: 40 h

Procedure:
A mixture of 20.0 g (62.5 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 1.0 g (15.4 mmol) of potassium cyanide and 100 ml of propargyl alcohol is stirred at 130° for 40 hours, about 50 ml of solvent being distilled off in vacuo after 16 hours and 50 ml of propargyl alcohol being added to the mixture. The mixture is subsequently evaporated to dryness in vacuo, the residue is taken up in chloroform, the chloroform solution is washed once with water and once with saturated sodium chloride solution and dried over magnesium sulphate. The magnesium sulphate is removed by filtration under suction and the chloroform solution is filtered through silica gel, elution being subsequently carried out with ethyl acetate. After evaporation of the eluate, the residue is recrystallized twice from chloroform/toluene and once from ethanol, there being obtained 2-propynyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3 -carboxylate of melting point 198°-200°.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CS(C)=O.CC(OC(C)=O)=O.CCOC(C)=O>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C:10]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 12 h
Yield: 94.8 %

Procedure:
(3R,4S,5R,6R)-3,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-ol (4) (2.00 g, 3.7 mmol, Senn Chemicals) was dissolved in solution of 12.0 mL DMSO and 8.0 mL Ac2O. After stirring for 12 h, the reaction was diluted with EtOAc, washed with H2O (1×), sat. NaHCO3 (1×), then dried (Na2SO4) and concentrated using high-vacuum to provide a syrup (1.89 g, 95%). LC/MS 100% (ELSD) tR=3.10 min, calcd for C34H34O6: 538.24, found 539.4 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:9]=[C:10]([CH3:12])[N:11]=2)[CH:6]=[CH:7][CH:8]=1.[K+].[Br-]>>[CH3:12][C:10]1[N:11]=[C:4]2[C:3]([CH:2]=[O:1])=[CH:8][CH:7]=[CH:6][N:5]2[CH:9]=1
Reactant: Cc1cn2cccc(CO)c2n1
Agent: [Br-]
Agent: [K+]
Product: Cc1cn2cccc(C=O)c2n1
Yield: 98 %

Procedure:
From 3b: reaction time 3 h: (yield: 98%); mp 123-125° C. (in Kaminski, J. J. and al. J. Med. Chem. 1989, 32, 1686-1700: 140-143° C.); IR (KBr) 1690, 1315 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.49 (s, 3H), 6.86 (t, 1H, J=7 Hz), 7.44 (s, 1H), 7.71 (d, 1H, J=7 Hz), 8.26 (d, 1H, J=7 Hz), 10.66 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.5, 110.1, 111.2, 123.2, 126.2, 130.0, 143.6, 145.2, 189.0; MS m/z 160 (M+, 30), 132 (100), 131 (49), 105 (25), 92 (22), 51 (20).
Reaction SMILES: [CH2:1]=[N:2][CH2:3][C:4]([CH3:11])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:5].Cl.[OH-].[Na+]>>[CH3:5][C:4]1([CH3:11])[CH2:3][NH:2][CH2:1][C:10]2=[CH:9][S:8][CH:7]=[C:6]12
Reactant: C=NCC(C)(C)c1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CNCc2cscc21

Procedure:
6.00 g (35.9 mmol) methylene-(2-methyl-2-thiophene-3-yl-propyl)-amine, 11.3 mL (45.3 mmol) 4M HCl and 11.8 mL (142 mmol) conc. HCl were stirred at RT over the weekend. The reaction mixture was made alkaline with 4M NaOH solution. The precipitate formed was suction filtered, washed with water and dried. The substance was purified through Alox. The product-containing fractions were combined and concentrated to dryness by rotary evaporation.
Reaction SMILES: [Na+].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[S:13]([O-:15])=[O:14].[CH3:16]I>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: CC(=O)Cc1ccc(F)c(S(=O)[O-])c1
Reactant: CI
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(F)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution comprising 2-fluoro-5-(2-oxo-propyl)-benzenesulfinic acid sodium salt (AG2) (15.43 g, 64.83 mmol) in DMF (300 ml) is treated with methyl iodide (18.45 g, 130 mmol). The reaction mixture is stirred at room temperature for 30 minutes. Purification is carried out by chromatography on silica (eluting with 4:1 hexane-ethyl acetate) to afford the titled compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[O:8])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[ClH:27]>>[ClH:27].[NH2:12][CH2:11][CH2:10][NH:9][C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:8]
Reactant: Cc1ccc(C(=O)NCCNC(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)NCCN)s1

Procedure:
14.9 g of t-butyl [2-(5-methylthiophene-2-carboxamido)ethyl]carbamate were reacted with trifluoroacetic acid in an analogous manner to that described in Example 2, paragraph 2. The residue was converted into the hydrochloride which was recrystallized from ethanol/ether, whereby there was obtained N-(2-aminoethyl)-5-methylthiophene-2-carboxamide hydrochloride as light beige crystals, m.p. 161°-162°.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:14]2[C@@H:10]([C:11](=[O:16])[O:12][C@H:13]2[CH3:15])[CH2:9][C@@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2.[H-].[CH3:18]CCCCC.CO.O.C(N(CC)CC)C>CCOCC.C(Cl)Cl.CO>[OH:1][C@H:2]1[C@@H:14]2[C@@H:10]([C@@H:11]([O:16][CH3:18])[O:12][C@H:13]2[CH3:15])[CH2:9][C@@H:8]2[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: CCCCCC
Reactant: C[C@@H]1OC(=O)[C@H]2C[C@H]3CCCC[C@@H]3[C@@H](O)[C@@H]12
Agent: [H-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: CO[C@H]1O[C@@H](C)[C@@H]2[C@H](O)[C@H]3CCCC[C@@H]3C[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To 1.88 g(8.38 mmol) of (3S,3aS,4R,4aS,8aR,9aS)-4-hydroxy-3-methyl-decahydronaphtho[2,3-c]furan-1(3H)-one in 200 ml of dehydrated ether solution were added dropwise 26.7 ml(3 equivalents) of diisobutylalumium hydride-hexane solution(0.94 M) at −78° C. under an atmosphere of argon. After stirring for about 1 hour at the same temperature, methanol-water mixed solution (10 ml+10 ml) was added dropwise slowly and the mixture was stirred for 1 hour at room temperature. Solvent was distilled off and 100 ml of ethyl acetate were added to the residue, which was filtered through celite, and the residue was washed with ethyl acetate(50 ml). Solvent was distilled off and 100 ml of saturated brine were added, which was extracted with methylene chloride(30 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off to obtain crude lactol form. This was dissolved into a mixed solution of 50 ml of dehydrated methanol with 50 ml of dehydrated methylene chloride, 1.55 ml(1.5 equivalents) of boron trifluoride-diethyl ether complex were added dropwise at −60° C. under an atmosphere of argon, and the mixture was stirred for about 12 hours while raising temperature naturally. To the reaction mixture were added 1.75 ml (1.5 equivalents) of triethylamine and, after stirring at room temperature, solvent was distilled of. To the residue was added 100 ml of cold dilute aqueous solution of sodium hydrogencarbonate, which was extracted with methylene chloride(30 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=2:1) to obtain 1.50 g of (1S,3S,3aS,4R,4aS,8aR,9aS)-4-hydroxy-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan (yield after two processes 74%).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15](O)=[O:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([C:26]1[CH:40]=[CH:39][C:29]([CH2:30][N:31]2[C:35]([CH2:36][CH2:37][NH2:38])=[CH:34][N:33]=[CH:32]2)=[CH:28][CH:27]=1)#[N:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C>[C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH:11]([C:15](=[O:16])[NH:38][CH2:37][CH2:36][C:35]3[N:31]([CH2:30][C:29]4[CH:39]=[CH:40][C:26]([C:24]#[N:25])=[CH:27][CH:28]=4)[CH:32]=[N:33][CH:34]=3)[CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1
Reactant: O=C(O)C1CCCN(CC(c2ccccc2)c2ccccc2)C1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)C2CCCN(CC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2,2-Diphenylethyl)-3-carboxy piperidine(472 mg, 1,52 mmol),3-(4-cyanobenzyl) histamine (456 mg, 1.52 mmol) (EXAMPLE 1, Step E) HOBT (216 mg, 1.60 mmol), EDC (307 mg, 1.60 mmol), and Et3N (637 uL, 4.57 mmol) were dissolved in DMF (10 mL) and was stirred overnight at ambient temperature. The solution was concentrated under reduced pressure and chromatographed (silica gel, 0.5-2% MeOH/CH2Cl2 with NH4OH) to give the title compound 1H NMR (CDCl3) δ7.96 (br s, 1H), 7.60 d, 2H, J=8 Hz), 7.46 (s, 1H), 7.09-7.37 (m, 12H), 6,74 (s, 1H), 5.20 (s, 2H), 4.26 (t, 1H, J=8 Hz), 3.05-3.17 (m, 2H), 2.93-3.04 (m,1H), 2.78-2.91 (m,2H), 2.49-2,61 (m 1H), 22.40-2.47 (m, 1H), 2.15-2.30 (m, 2H), 1.95-2.14 (m, 2H), 1.86 (d, 1H, J=12 Hz), 1.29-1.55 (m, 3H). FAB MS 518 (M+1)
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].Cl[C:8]1[N:12]=[C:11]([CH:13]2[CH2:18][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[CH2:16][N:15]([C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[CH2:14]2)[O:10][N:9]=1>O1CCOCC1>[N:31]1([C:29]([N:15]2[CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=3)[CH2:18][CH:13]([C:11]3[O:10][N:9]=[C:8]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])[N:12]=3)[CH2:14]2)=[O:30])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: OCC(F)(F)F
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: C1COCCO1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(OCC(F)(F)F)no2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 112 mg (1.12 mmol) of 2,2,2-trifluoroethanol in 4.00 ml of 1,4-dioxane were added, at RT, 4 Å molecular sieve and 0.23 ml (0.45 mmol; 2 M solution in THF) of phosphazene P4 base. Subsequently, 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 2.0 ml of 1,4-dioxane were added and the reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered, diluted with dichloromethane and washed with 1 N aqueous hydrogen chloride solution. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by means of preparative HPLC. Yield: 12.4 mg (11% of theory)
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17]CC2C=CC=CC=2)=[O:16])=[C:13]([O:25]CC2C=CC=CC=2)[N:12]=[C:11]([C:33]2[CH:41]=[C:40]3[C:36]([C:37]4[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][C:38]=4[NH:39]3)=[CH:35][CH:34]=2)[C:10]=1[CH2:53][CH3:54])C1C=CC=CC=1>C(O)(C(F)(F)F)=O.[SiH](C(C)C)(C(C)C)C(C)C>[CH2:53]([C:10]1[C:9]([OH:8])=[C:14]([C:15]([OH:17])=[O:16])[C:13](=[O:25])[NH:12][C:11]=1[C:33]1[CH:41]=[C:40]2[C:36]([C:37]3[CH2:45][CH2:44][NH:43][CH2:42][C:38]=3[NH:39]2)=[CH:35][CH:34]=1)[CH3:54]
Reactant: CCc1c(-c2ccc3c4c([nH]c3c2)CN(C(=O)OC(C)(C)C)CC4)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCc1c(-c2ccc3c4c([nH]c3c2)CNCC4)[nH]c(=O)c(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 104.8 %

Procedure:
A mixture of tert-butyl 7-(4,6-bis(benzyloxy)-5-(benzyloxycarbonyl)-3-ethylpyridin-2-yl)-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (20 mg, 0.027 mmol) in TFA (0.2 mL) and TIPSH (0.2 mL) was stirred at room temperature for 15 h. The solvents were removed and the residue was stirred in 10% MeOH in CH2Cl2 (0.5 mL). The resulting solid was collected by filtration and washed with CH2Cl2 to give the title compound as an off-white solid (10 mg, TFA salt, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8]([C:10]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC)=O)=C(C)[NH:14][C:15]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1>C(O)C>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16])=[CH:4][CH:3]=1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(Cl)cc2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(Cl)cc1
Yield: 72 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 4-chlorobenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-chlorobenzyl ester of melting point 169° C (from ethanol).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:7][CH:8]=2)[N:3]=1.[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)=[O:35])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.CCO>[CH3:24][N:25]([CH3:53])[C:26](=[O:52])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([C:2]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[C:9]4[C:4](=[CH:5][C:6]([C:18]5[O:19][C:20]([CH3:23])=[CH:21][CH:22]=5)=[CH:7][CH:8]=4)[N:3]=3)=[CH:41][CH:42]=2)=[O:35])=[CH:29][CH:28]=1
Reactant: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)Nc5ccc(C(=O)N(C)C)cc5)cc4)nc3c2)o1
Temperature: 95 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
To a 50 mL round bottom flask, 2-chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (1.4 g, 0.0036 mol), N,N-dimethyl-4-{3-{4-(4,4,5,5,-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ureido}-benzamide (2.25 g, 0.0055 mol), sodium carbonate (0.775 g, 0.0073 mol), toluene (12 mL), EtOH (12 mL) and water (12 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd (PPh3)2Cl2 (128 mg, 0.000023 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 0-4% MeOH in chloroform) followed by preparative HPLC (0.1% TFA in water and ACN) to yield the title compound [0.65 g, 27%]. 1H NMR (400 MHz, DMSO-d6): δ 9.49 (brs, 1H), 9.27 (brs, 1H), 8.30 (d, J=8.8 Hz, 2H), 8.11 (t, J=9.2 Hz, 2H), 7.85 (d, J=8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.52 (d, J=8.8, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.22 (d, J=3.2 Hz, 1H), 6.37 (s, 1H), 4.22 (brs, 4H), 3.83 (brs, 4H), 2.95 (s, 6H), 2.40 (s, 3H); LC-MS (ESI): Calculated mass: 576.2; Observed mass: 576.7 [M+H]+ (RT: 0.64 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:10]
Reactant: C1COCCN1
Reactant: O=C(O)c1cnccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1cnccc1Cl)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
Combine 4-chloronicotinic acid (0.10 g, 6.0 mmol) and 1,1′-carbonyldiimidazole (0.97 g, 6.0 mmol) in dry THF (15 mL). Stir at room temperature under nitrogen for 90 min. Add morpholine (1.58 mL, 18.0 mmol) and stir at room temperature under nitrogen for 15 hours. Dilute with dichloromethane, wash with saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride. Separate the layers and dry the organic layer over magnesium sulfate. Concentrate in vacuo. Purify the crude residue by column chromatography [5% to 25% (10% 2 M ammonia/methanol solution in dichloromethane)/dichloromethane] to give the title compound (1.17 g, 86%). MS (ES) m/z 227 [M+1]+.