Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32][CH3:33])=[O:31])[CH2:7]1)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[K+]>O1CCCC1>[C:24]1([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C@@H:9]3[C@@H:8]([C:30]([O:32][CH3:33])=[O:31])[CH2:7][C@H:6]([S:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:11][N:10]3[C:12]([O:14][CH3:15])=[O:13])=[O:17])[CH2:19][CH2:20]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)[C@H]1C[C@@H](OS(C)(=O)=O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Sc2ccccc2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of dimethyl (2S,3S,5R)-5-[(methylsulfonyl)oxy]-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (50.0 mg, 0.000103 mol) and benzenethiol (0.0149 mL, 0.000145 mol) in tetrahydrofuran (0.50 mL, 0.0062 mol) was added 1.00 M of potassium tert-butoxide in tetrahydrofuran (0.150 mL). The mixture was stirred at rt overnight. The reaction mixture was carried directly into next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([OH:41])=O.CCN(C(C)C)C(C)C.O[NH:56][C:57](=[NH:71])[CH2:58][S:59][C:60]1[N:64]([CH3:65])[C:63]([C:66]2[S:67][CH:68]=[CH:69][CH:70]=2)=[N:62][N:61]=1>CN(C=O)C.O>[CH3:35][O:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]1[O:41][N:71]=[C:57]([CH2:58][S:59][C:60]2[N:64]([CH3:65])[C:63]([C:66]3[S:67][CH:68]=[CH:69][CH:70]=3)=[N:62][N:61]=2)[N:56]=1
Reactant: Cn1c(SCC(=N)NO)nnc1-c1cccs1
Reactant: COc1ccccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccccc1-c1nc(CSc2nnc(-c3cccs3)n2C)no1
Temperature: 25 °C
Reaction time: 7 h
Yield: 1.3 %

Procedure:
HBTU (171 mg, 0.45 mmol) and HOBT (8 mg, 0.06 mmol) were added to a solution of 2-methoxy benzoic acid (68 mg, 0.45 mmol) and DIPEA (192 ml, 1.11 mmol) in DMF (3 ml). After 10 min N-hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamidine (100 mg, 0.37 mmol) was added. The reaction mixture was stirred at RT for 7 h and then at 110° C. over night. After cooling the reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried and concentrated. Flash chromatography (heptane/EtOAc 1:2) afforded 1.9 mg (11%) of the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][C:10]2([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=3)[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]2=[O:19])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=3)[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][C:11]2=[O:19])=[CH:31][CH:32]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(CC2(Cc3ccc(C(=O)OC)cc3)C(=O)N=C3C=CC=CN32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CC2(Cc3ccc(C(=O)O)cc3)C(=O)N=C3C=CC=CN32)cc1
Temperature: 25 °C
Yield: 71 %

Procedure:
300 mg (0.7 mmol) of 3,3-bis(4-methoxycarbonylbenzyl)-imidazo[1,2-a]pyridin-2(3H)-one prepared in the similar way to that of Example 1 was heated at 70° C. for 3 hours in a mixture of 8 ml of 2N-sodium hydroxide and 2 ml of ethanol. The reaction mixture was allowed to cool to room temperature and washed with methylene chloride. The water layer was adjusted by diluted hydrochloric acid to pH5 and the precipitated deposit was filtered out and dried, thus obtaining 200 mg (yield: 71%) of the titled compound.
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[CH:6][NH:5][C:4]=2[CH:3]=[C:2]1[C:9]([O:11]CC)=[O:10].[C:14]1(=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[O-]CC.[Na+].Cl>CCO>[C:14]1([C:7]2[C:8]3[S:1][C:2]([C:9]([OH:11])=[O:10])=[CH:3][C:4]=3[NH:5][CH:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=1
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)c1cc2[nH]ccc2s1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1cc2[nH]cc(C3=CCCCC3)c2s1
Yield: 98 %

Procedure:
A solution (0.25 M) of ethyl 4H-thieno[3,2-b]pyrrole-2-carboxylate in EtOH was treated with cyclohexanone (2 eq.) and sodium ethoxide (2.05 eq.) then heated to reflux for 4 h. After cooling down, it was acidified with aqueous HCl (6 N) and the precipitate was filtered and dried, affording the title compound (98%) as a solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.Cl.[F:35][C:36]([F:60])([F:59])[C:37]1[CH:38]=[CH:39][C:40]([O:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][C:51]([N:53]3[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]3)=[O:52])=[CH:46][CH:45]=2)=[N:41][CH:42]=1>CN(C=O)C.C(N(CC)CC)C.O>[F:60][C:36]([F:35])([F:59])[C:37]1[CH:38]=[CH:39][C:40]([O:43][C:44]2[CH:45]=[CH:46][C:47]([O:50][C:51]([N:53]3[CH2:54][CH2:55][N:56]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=4)[CH2:57][CH2:58]3)=[O:52])=[CH:48][CH:49]=2)=[N:41][CH:42]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1ccccn1)N1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1
Reaction time: 0.83 h

Procedure:
Triethylamine (0.026 ml) was added to a stirred solution of (pyridin-2-yl)acetic acid hydrochloride (0.033 g, 0.19 mmol) in DMF (2.5 ml) at 0° C. 1-Hydroxy-benzotriazole containing 8% of water (0.034 g) and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.044 g) was added and the mixture was stirred for 50 min. Piperazine-1-carboxylic acid 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl ester hydrochloride (0.070 g) in a mixture of DMF (1 ml) and triethylamine (0.032 ml) was added and stirring was continued over night at room temperature. The solvent was removed in vacuum and the residue was partitioned between dichloromethane (10 ml) and water (10 ml). The organic phase was washed with water (10 ml), dried over sodium sulfate, filtered and evaporated. The residue was triturated with etherpetroleumsether 1:1 and the (2+1 ml). The residue was dried to give the title compound. White solid, m.p. 143–146° C.; HPLC-MS m/z: IR (KBr) □ 1732 (C═O), 1643 (C═O).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[O:10])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C.[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47]1[N:51]=[C:50]([CH2:52][CH2:53][C:54](O)=[O:55])[O:49][N:48]=1>C(OCC)(=O)C.O.CN(C=O)C.C(N(CC)CC)C>[CH3:16][N:14]([CH3:15])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:54](=[O:55])[CH2:53][CH2:52][C:50]2[O:49][N:48]=[C:47]([C:38]3[CH:39]=[CH:40][C:41]4[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH:37]=3)[N:51]=2)=[CH:7][CH:6]=1
Reactant: O=C(O)CCc1nc(-c2ccc3ccccc3c2)no1
Reactant: CN(C)CCNC(=O)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)Cc1ccc(NC(=O)CCc2nc(-c3ccc4ccccc4c3)no2)cc1
Reaction time: 5 h
Yield: 35.3 %

Procedure:
2-(4-Aminophenyl)-N-[2-(dimethylamino)ethyl]acetamide (221 mg), WSC (249 mg), 1-hydroxybenzotrizole (199 mg), triethylamine (0.4 ml), and dimethylaminopyridine (244 mg) were added to a DMF (5 ml) solution of 3-[3-(2-naphthyl)-1,2,4-oxadiazol-5-yl]propionic acid (268 mg), which was stirred for 5 hours. The reaction mixture was poured into water, and extraction was conducted using ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried over sodium sulfate, and then concentrated. The residue was recrystallized from methanol, to give the titled compound (166 mg).
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2].CC(C)([O-])C.[K+].[Cl:24][C:25]1[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1.Cl>CN(C=O)C>[ClH:24].[C:1]([C:4]1[O:8][C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[N:10]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: O=C(O)c1ccc(-c2n[nH]c3ccccc23)o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2nn(-c3nccc(C(F)(F)F)n3)c3ccccc23)o1

Procedure:
1.3 g (5.7 mmol) of 3-(5-carboxy-2-furyl)indazole together with 1.3 g (11.4 mmol) of potassium tert-butoxide were dissolved in 5 ml of dry DMF and admixed with 2-chloro-4-trifluoromethylpyrimidine dissolved in 5 ml of DMF. The mixture was stirred at 60° C. the hydrochloride was precipitated from the aqueous phase by addition of 1 N hydrochloric acid. This gave 420 mg (25%) of the title compound. m.p.: 258-261° C.
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH3:11])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.Cl.[NH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C([O-])(=O)C.[Na+]>C1(C)C=CC=CC=1>[CH2:28]([O:27][C:25]([CH2:24][CH2:23][CH2:22][N:21]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])=[O:26])[CH3:29]
Reactant: CCOC(=O)CCCN
Reactant: CC(=O)CCC(=O)CN1C(=O)c2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCn1c(C)ccc1CN1C(=O)c2ccccc2C1=O

Procedure:
3.9 g (0.015 mol) of 6-phthalimido-2,5-hexanedione, 2.5 g ((0.015 mol) of ethyl 4-aminobutyrate hydrochloride and 1.3 g (0.015 mol) of sodium acetate are stirred in 50 ml of toluene at 60° C. for 23 hours. After the mixture has been concentrated, it is worked up as in Example 22.
Reaction SMILES: S([O-])([O-])(=O)=O.[Zr+4:6].S([O-])([O-])(=O)=O.[P].[OH:13][P:14]([OH:17])([OH:16])=[O:15].[OH-].[Na+]>O>[P:14]([O-:17])([O-:16])([O-:15])=[O:13].[Zr+4:6].[P:14]([O-:17])([O-:16])([O-:15])=[O:13].[P:14]([O-:17])([O-:16])([O-:15])=[O:13].[P:14]([O-:17])([O-:16])([O-:15])=[O:13].[Zr+4:6].[Zr+4:6]
Reactant: O=P(O)(O)O
Agent: [Zr+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Amorphous zirconium phosphate was prepared in all the examples. In this example the material was prepared according to the following procedure. In the first stage, a slurry containing 440 g of basic zirconium sulfate (40% ZrO2) (MEI, HCP PP142A), with a predetermined particle size distribution ranging from 50 to 60 microns, in a phosphorus-containing solution was made. The phosphorus-containing solution had the following composition: 3.3 kg of water, 402 g of 75 wt % H3PO4, 380 g of 30 wt % NaOH and 45 g of Na4SiO4. The slurry was transferred into an autoclave, sealed and heated at 160° C. for 3 hours under constant stirring. The resulting product of conversion was filtered, washed with 0.5 kg of water and re-slurried in 2 L of 1 M H2SO4. The zirconium phosphate slurry in sulfuric acid was heated to the boiling point and kept at this temperature for 1 hour. After cooling down, the zirconium phosphate was filtered, washed with 0.5 kg of water and re-slurried in 1 L of water. To the ZrP suspension a 30 wt % NaOH solution was added gradually for 30 to 40 minutes to raise the pH to 7.0. Then, the zirconium phosphate was filtered, washed with 1 kg of water and dried at 150° C. for 12 hours in air.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].COC1N=C(OC)N=C([O:17][C:18](=O)[C:19]2[CH:24]=[C:23]([CH3:25])[C:22](/[CH:26]=[CH:27]/[S:28]([N:31]3[CH2:47][CH2:46][C:34]4([N:38]=[C:37]([CH:39]5[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]5)[NH:36][C:35]4=[O:45])[CH2:33][CH2:32]3)(=[O:30])=[O:29])=[C:21]([CH3:48])[CH:20]=2)N=1.C(N(CC)CC)C.O>C(#N)C>[CH:39]1([C:37]2[NH:36][C:35](=[O:45])[C:34]3([CH2:33][CH2:32][N:31]([S:28](/[CH:27]=[CH:26]/[C:22]4[C:23]([CH3:25])=[CH:24][C:19]([C:18]([N:3]5[CH2:4][CH2:5][O:1][C:2]5=[O:6])=[O:17])=[CH:20][C:21]=4[CH3:48])(=[O:30])=[O:29])[CH2:47][CH2:46]3)[N:38]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=C1NCCO1
Reactant: COc1nc(OC)nc(OC(=O)c2cc(C)c(/C=C/S(=O)(=O)N3CCC4(CC3)N=C(C3CCCCC3)NC4=O)c(C)c2)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)N2CCOC2=O)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)N=C(C1CCCCC1)NC2=O
Temperature: 80 °C
Reaction time: 15 h
Yield: 33.6 %

Procedure:
Oxazolidin-2-one (47 mg, 0.53 mmol) was added to a solution of 4-[(E)-2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-vinyl]-3,5-dimethyl-benzoic acid 4,6-dimethoxy-[1,3,5]triazin-2-yl ester (109 mg, 0.17 mmol) and triethylamine (0.12 ml, 0.88 mmol) in anhydrous acetonitrile (1 ml), and the mixture was heated with stirring at 80° C. for 15 hours. The mixture was cooled and water was then added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 2-cyclohexyl-8-{(E)-2-[2,6-dimethyl-4-(2-oxo-oxazolidine-3-carbonyl)-phenyl]-ethenesulfonyl}-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (31 mg, 32%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:3]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Clc1cc(Cl)nc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.56 ml (4.87 mmoles) of 2,4,6-trichloropyrimidine diluted with 20 ml of tetrahydrofuran is dropwise added to a solution of 2.0 g (5.12 mmoles) of 1- (3α,16α)-eburnamenine-14-carbonyl!piperazine in 50 ml of tetrahydrofuran at 0° C. After stirring at room temperature for 12 hours the reaction mixture is evaporated to dryness. The residue is distributed between 100 ml of chloroform and 25 ml of 5% sodium hydroxide solution. After separation the organic phase is dried, evaporated and the evaporation residue is subjected to chromatography on silica gel column. By using a chloroform/methanol mixture (100:0→99:1) as eluent, the less polar 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(4,6-dichloro-2-pyrimidinyl)piperazine is first obtained in a yield of 0.325 g (12.7%), m.p.: 100°-107° C. (after recrystallization from ether). By further elution the more polar 1- (3α,16α)-eburnamenine-14-carbonyl!-4-(2,4-dichloro-6-pyrimidinyl)piperazine is obtained in a yield of 2.26 g (88.3%), m.p.: 165°-175° C. (after recrystallization from ether).
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH:16]1([CH2:15][NH:10][C:8]2[S:9][C:5]3[CH:4]=[C:3]([O:12][CH3:13])[C:2]([F:1])=[CH:11][C:6]=3[N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc2sc(N)nc2cc1F
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2sc(NCC3CCCCC3)nc2cc1F
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
To the solution of 5-fluoro-6-methoxybenzo[d]thiazol-2-amine (350 mg, 1.76 mmol, 1.0 eq) in 2 mL of NMP was added bromomethyl cyclohexane (370 μL, 2.65 mmol, 1.5 eq) and potassium carbonate (366 mg, 2.65 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at 80° C. for 24 hours with subsequent addition of reagents till reaction completion and thereafter quenched with saturated sodium bicarbonate solution (100 mL) which was then extracted with ethyl acetate (125 mL×3), combined organic layers dried over sodium sulfate, filtered and condensed under reduced pressure. Purification of the crude over ISCO using slow gradient of 0%-50% ethyl acetate-hexane gave 310 mg of product in 60% yield. LC/MS (m/z) [295.1] (MH+)
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:19])[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH3:19][C:12]1[CH:17]=[C:16]([CH:15]=[C:14]([CH3:18])[CH:13]=1)[CH:10]([OH:11])[C:8](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1cc(C)cc(C(O)C(=O)c2ccccc2)c1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and m-xylene (0.49 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 30 minutes. Using the same procedure as in Example 1, 3', 5'-dimethylbenzoin was obtained as a light-yellow oil (363.2 mg, 75.3% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:24]C(=O)OC(C)(C)C)[C:10](=[O:23])[NH:11][C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:14][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:24][C@@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:10]([NH:11][C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)=[N:14][CH:13]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cnc(-c2ccncc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(F)cc1)C(=O)Nc1cnc(-c2ccncc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of (S)-tert-butyl 3-(4-fluorophenyl)-1-oxo-1-(2-(pyridin-4-yl)thiazol-5-ylamino)propan-2-ylcarbamate (0.250 g, 0.565 mmol) in DCM (10.0 ml, 155 mmol) was added TFA (2.50 ml, 32.4 mmol). The resulting mixture was allowed to stir at rt for 4 hours. The mixture was concentrated and the residue was purified by HPLC to give 145 mg of (S)-2-amino-3-(4-fluorophenyl)-N-(2-(pyridin-4-yl)thiazol-5-yl)propanamide 5.2B. 400 MHz 1H NMR (CD3OD) δ: 8.79 (d, J=8.0 Hz, 2H), 8.37 (d, J=8.0 Hz, 2H), 7.86 (s, 1H), 7.30 (dd, J=8.0, 4.0 Hz, 2H), 7.08 (dd, J=12, 8.0 Hz, 2H), 4.37 (dd, J=8.0, 8.0 Hz, 1H), 3.34 (obscured dd, 1H), 3.23 (dd, J=12.0, 8.0 Hz, 1H), LCMS (ES+) m/z 343.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:16]2[CH:20]=[CH:19][CH:18]=[N:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: c1cn[nH]c1
Product: CC(C)(C)OC(=O)N1CCC(Cn2cccn2)CC1

Procedure:
By a similar manner to Reference Example 29, 1-tert-butoxycarbonyl-piperidin-4-methanol (1.08 g, 5.0 mmol) was reacted with pyrazole (1.02 g, 1.5 mmol) to give the titled compound as pale yellow oily substance (980 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH3:29].N>>[CH2:26]([N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCBr
Reactant: Clc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(Cl)c1
Agent: N
Product: CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (21 mg, 61%) from (7aS,11aR)-2-(2,4-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 1-bromobutane (23 mg, 0.17 mmol). MS (CI, NH3): 415.1 (base, M+H).
Reaction SMILES: C[O-].[Na+].[Na].[CH:5](=[N:12][NH:13][C:14](N)=[NH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(O[C:20](=[O:29])[CH2:21][NH:22][CH2:23][C:24]([O:26][CH2:27]C)=[O:25])C>CO.C(Cl)(Cl)Cl.O>[CH:5](=[N:12][N:13]=[C:14]1[NH:15][C:20](=[O:29])[CH2:21][N:22]1[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CNCC(=O)OCC
Reactant: N=C(N)NN=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)CN1CC(=O)NC1=NN=Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
To a methanol solution of sodium methoxide prepared by dissolving 2.30 g of metal sodium in 150 ml of methanol was added 5.70 g of benzylideneaminoguanidine, and, after stirring the mixture for one hour at room temperature, 11.35 g of iminodiacetic acid diethyl ester was added thereto, followed by refluxing under heating for 17 hours. After cooling the reaction mixture, water and chloroform were added thereto to distribute the mixture between aqueous and organic layers and, then, the aqueous layer was extracted three times with chloroform. The organic layer was combined with the extract. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, and the residue was charged on silica gel column chromatography, followed by elution with a mixed solvent of chloroform and methanol (100:1 (v/v)). Thus 2.61 g of 2-benzylidenehydrazono-1-methoxycarbonylmethylimidazolidin-4-one was obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.[CH3:11][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)[C@H]1CC[C@@H](O)CC1
Reaction time: 3 h

Procedure:
2 g of cis-4-hydroxycyclohexanecarboxylic acid (13.87 mmol, 1 eq.) are placed in 50 mL of a 4/1 mixture of toluene/methanol at room temperature. Trimethylsilyl-diazomethane (111 mL, 221.96 mmol, 16 eq.) is poured into the reaction medium with stirring. After 3 hours at room temperature, the reaction medium is evaporated to give 2.6 g of methyl cis-4-hydroxycyclohexanecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:13]2[N+:14]([O-])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:4][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1.P(Cl)(Cl)Cl.O>C1C=CC=CC=1>[CH3:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:4][C:5]([CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(=O)OCc1ccc(C)c(-c2cccc[n+]2[O-])n1
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)OCc1ccc(C)c(-c2ccccn2)n1
Temperature: 23 °C

Procedure:
2.1 g (8.1 mmols) of 3-methyl-6-acetoxymethyl-2,2'-bipyridine 1'-oxide are dissolved in 20 ml of benzene at 45° C., and 1.43 g (10.4 mmols) of phosphorus trichloride are added dropwise under an atmosphere of nitrogen. Subsequently, the mixture is boiled under reflux for 30 minutes. After cooling to 23° C., 35 ml of water are added and the benzene phase is separated off. The water phase is washed with twice 15 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. After distillation in a bulb tube oven at 125° C./0.13 Pa, 1.51 g (77% of theory) of 3-methyl-6-acetoxymethyl-2,2'-bipyridine are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2c[nH]c3ccncc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (20 mg, 0.094 mmol), benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.