Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=1)[N:34]=[C:33]([CH:42]=O)[CH:32]=[CH:31]2>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:42]/[C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[C:36]([O:38][CH:39]([CH3:41])[CH3:40])[CH:37]=[C:28]([F:27])[CH:29]=3)[N:34]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: CC(C)Oc1cc(F)cc2ccc(C=O)nc12
Solvent: CCO
Product: CC(C)Oc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Yield: 99.9 %

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (100 mg, 0.266 mmol) and 6-fluoro-8-isopropoxyquinoline-2-carbaldehyde (62.1 mg, 0.266 mmol) were stirred in ethanol (5 mL) for 72 hours at ambient temperature. The reaction was concentrated under reduced pressure to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((6-fluoro-8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (157 mg, 99.8% yield) as a yellow paste.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:11][C:10]([OH:15])([C:12](N)=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:22].[Na+]>C(O)C.O>[C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH2:11][C:10]([OH:15])([C:12]([OH:22])=[O:13])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxamide (1.1 g, 3.90 mmol) was treated with 10% sodium hydroxide in ethanol (15 mL) and water (2 mL) at reflux for 2 h and then was concentrated in vacuo. The residue was neutralized with 1 N hydrochloric acid (pH ˜7) and the precipitate was collected by filtration and lyophilized to afford 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) which was used without further purification: 1H NMR (400 MHz, d6-DMSO): 7.45-7.40 (m, 4H), 7.31-7.25 (m, 4H), 7.21-7.15 (m, 2H), 4.52 (s, 1H), 3.46 (dd, 2H), 3.02 (dd, 2H); MS (EI) for C17H17NO3: 284 (MH+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21](=[O:32])[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][C:29](=O)C)C=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:35]CCCCCCCC(O)=O>>[Br:35][CH2:29][CH2:28][CH2:24][CH2:25][CH2:26][CH2:27][CH2:22][C:21]([NH:20][CH2:19][C:10]1[C:11]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][C:9]=1[CH2:33][CH3:34])=[O:32]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(CC(C)=O)c1
Reactant: O=C(O)CCCCCCCBr
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCCCCCBr

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using 8-bromo-octanoic acid in place of 3-(2-oxopropyl)benzoic acid. ES/MS calcd. for C24H39BrN5O2+ 508.2. found m/z=508.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=O)[CH3:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(N(CC)CC)C.Cl.[OH-:25].[NH4+:26]>C(O)C>[OH:25][N:26]=[C:14]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]2)[CH3:15]
Reactant: COC(=O)N1CCc2cc(C(C)=O)ccc21
Reactant: [OH-]
Reactant: [NH4+]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2cc(C(C)=NO)ccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A mixture of 5-acetyl-2,3-dihydroindole-1-carboxylic acid methyl ester, Preparation 18 (6.57 g, 30 mmol), triethylamine (6.06 g, 60 mmol), and ammonium hydroxide hydrochloride (4.2 g, 60 mmol) in ethanol (80 mL) was stirred under reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was extracted with CH2Cl2 (1×60 mL), and the organic layer was dried over anhydrous magnesium sulfate, filtered, and the resultant filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography on silica eluting with ethyl acetate/hexane (30%) to provide the title product (6.3 g, 90%) as a solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:4]=1.[N:14]#[C:15][NH2:16]>CCO>[NH:2]([C:3]1[CH:7]=[N:6][N:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[N:13])[N:4]=1)[C:15]([NH2:16])=[NH:14]
Reactant: N#CCCCCn1ncc(N)n1
Reactant: N#CN
Agent: Cl
Solvent: CCO
Product: N#CCCCCn1ncc(NC(=N)N)n1
Reaction time: 2 h

Procedure:
A solution 5-(4-amino-1,2,3-triazol-2-yl)valeronitrile hydrochloride (2.01 g.) in EtOH (15 ml.) was treated with cyanamide (0.42 g.) and the solution heated under reflux for 4.5 hours. A further 0.1 g. of cyanamide was added and heating under reflux was continued for 2 hours. The solution was evaporated and the residue basified with ammonia and continuously extracted for 24 hours with EtOAc to give a yellow oil which was purified by medium pressure chromatography using chloroform/MeOH/aqueous ammonia (s.g. 0.880) 8:2:0.1 v/v/v as eluant to give 5-(4-guanidino-1,2,3-triazol-2-yl)valeronitrile as a colourless oil (0.45 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:13]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=1)=[O:14]>>[NH2:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][CH:3]=1)[CH:13]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])=[CH:17][CH:16]=1)[OH:14]
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Reactant: Nc1ccccc1
Agent: [Li]CCCC
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(N)c2)cc1
Yield: 25.2 %

Procedure:
The protected aniline (23.64 g. 0.101 mol) was treated with n-butyllithium (1.5M in hexane, 66 mL, 0.101 mol) and 4-formyl-N,N-diethylbenzamide (20.70 g, 0.101 mol) as in Example11. Chromatography of the crude product on silica gel (Waters Prep 500, dichloromethane:ethanol/100:1-3) gave 7.59 g (25%) of 4-(3-amino-α-hydroxybenzyl)-N,N-diethylbenzamide as a light yellow hygroscopic solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[C:35]([CH3:37])[C:20]([O:21][S:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=3)(=[O:24])=[O:23])=[C:19]([CH3:38])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:39](OC(=O)C)(=[O:41])[CH3:40].[I-].[Mg+2].[I-]>C(OCC)C>[C:39]([O:34][C:27]1[CH:26]=[C:25]([S:22]([O:21][C:20]2[C:35]([CH3:37])=[CH:36][C:17]([C:9]3[C:10]4[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=4[C:2]([Br:1])=[C:3]4[C:8]=3[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:18][C:19]=2[CH3:38])(=[O:24])=[O:23])[CH:33]=[CH:32][C:28]=1[C:29]([OH:31])=[O:30])(=[O:41])[CH3:40]
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: [I-]
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(=O)Oc1cc(S(=O)(=O)Oc2c(C)cc(-c3c4ccccc4c(Br)c4sc(C)c(C)c34)cc2C)ccc1C(=O)O
Temperature: 25 °C
Yield: 76 %

Procedure:
A stirred suspension containing 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (0.350 g, 0.572 mmol), acetic anhydride (4.55 mL) and magnesium iodide (0.159 g, 0.572 mmol) in anhydrous ethyl ether (10.0 mL, 0.05M) was refluxed for 0.5 h. The reaction was cooled to ambient temperature, quenched with H2O (150 mL), extracted with ether and concentrated. The crude product was dissolved in THF:H2O (1:1, 10 mL) and refluxed for 1 h. The reaction was cooled to ambient temperature, diluted with H2O (50 mL) and extracted with ether and EtOAc. The combined organic extracts were concentrated and purified on 2% H3PO4 /MeOH treated silica gel, eluting with a 20 & 25% EtOAc/pet. ether step gradient to give 0.298 g (76%) of the title compound as a white solid; 1H NMR (DMSO-d6) δ 1.58 (s, 3 H), 2.15 (s, 6 H), 2.30 (s, 3 H), 2.45 (s, 3 H), 7.20 (s, 2 H), 7.46-7.54 (m, 2 H), 7.67 (t, 1 H), 7.94 (d, 1 H), 8.05 (dd, 1 H), 8.20-8.25 (m, 2 H), 13.75-13.95 (br.s., 1 H). mass spectrum (-ESI), m/z 651/653 (M-H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1c[nH]c2ccccc12)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from commercial 3-indolecarbaldehyde and acetophenone, 3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one was obtained as yellow solid.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1(OC)C=CC=CC=1.CCS.[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S.[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:11]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:7]=[CH:8]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: CCS
Product: C1=Cc2ccccc2C1

Procedure:
Treatment of p-methoxydeoxybenzoic (32) (FIG. 4) with PCl5 in refluxing benzene provided p-methoxy-α'-chlorostilbene 33 (Nagano, 1955), which underwent Friedel-Crafts conditions with anisole to furnish the triarylethylene 34. The carbonyl group in deoxybenzoic 32 was converted to a gem-dichloride intermediate, using phosphorus pentachloride, and with the subsequent elimination of HCl, the vinyl chloride 33 was obtained. Compound 32 was prepared using Friedel-Crafts conditions involving phenylacetyl chloride and anisole in carbon disulfide and aluminum chloride (BUCK, J. S. and IDE, W. S. (1932), "The isomeric desoxybenzanisoins", Journal of the American Chemical Society, 54, 3012). Demethylation of 35 was accomplished with EtSH/AlCl3, and 36 was isolated by column chromatography. Drying of phenol 36 at a high temperature resulted in the formation of an indene, which was observed previously (MAGARIAN, R. A., MELTON, S. AND NATARELLI, G. (1972), "2-Chloro-1-phenylindene from 1,1-dichloro-trans-2,3-diphenylcyclopropane", Journal of Pharmaceutical Sciences, 61, 1216). Compound 36 was isolated as the diacetate (37) using column chromatography.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:15][C:14](=[O:16])[CH:13]([CH3:17])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CO
Reactant: CC(CNC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)CNC(=O)OCc1ccccc1

Procedure:
22.6 g of 3-benzyloxycarbonylamino-2(R,S)-methylpropionic acid are left to stand for 24 hours in 230 ml of methanol with a few drops of concentrated sulfuric acid. The reaction mixture is concentrated by evaporation and the residue is purified by FC (220 g of silica gel, dichloromethane). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.60.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CS(C)=O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:14][CH2:15][CH:16]([CH:19]=[O:20])[CH2:17][CH2:18]1
Reactant: OCC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=CC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a solution of {1-[2,4-bis(trifluoromethyl)phenyl]piperidin-4-yl}methanol (2.41 g) and triethylamine (3.08 mL) in dimethyl sulfoxide (30 mL) was added sulfur trioxide pyridine complex (3.52 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated, washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.60 g).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][C@H:31]1[NH:36][C@@H:35]([CH3:37])[CH2:34][N:33]([C:38]2[N:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]=2)[CH2:32]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:36]3[C@H:35]([CH3:37])[CH2:34][N:33]([C:38]4[N:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[CH2:32][C@@H:31]3[CH3:30])[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: C[C@@H]1CN(c2ncc3ccccc3n2)C[C@H](C)N1CCCCC1(C(=O)NCc2ccc(F)cc2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-(cis-3,5-dimethyl-piperazin-1-yl)-quinazoline.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].[NH4+].[OH-].[NH2:45][CH2:46][CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.CN(C=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C@@H:2]([NH:1][C:31]([NH:45][CH2:46][CH2:47][C:48]2[N:52]=[CH:51][NH:50][CH:49]=2)=[O:32])[C:3]([N:5]2[CH2:10][CH2:9][C:8]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)=[O:4])=[CH:24][CH:25]=1
Reactant: NCCc1c[nH]cn1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.9 %

Procedure:
200 mg (0.48 mmol) of ethyl 1-[(R)-2-amino-3-(4-chlorophenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate and 105 mg (0.52 mmol) of para-nitrophenyl chloroformate are dissolved in 5 mL of dichloromethane. The mixture is stirred for 2 hours at room temperature and the solution is then poured into aqueous 20% NH4OH solution and extracted with dichloromethane. The organic phase is washed with water and then dried over sodium sulfate and evaporated. The colourless oil obtained is diluted in 5 mL of DMF, the mixture is heated to 80° C., 58 mg (0.52 mmol) of histamine are then added and the solution is stirred for 5 minutes at 80° C. and for 10 minutes at room temperature. The reaction is stopped by adding aqueous 5% citric acid solution, and the organic products are extracted with DCM. The organic phase is washed with aqueous 1N NaOH solution and then with water. After drying over sodium sulfate and evaporation, the crude product obtained is chromatographed on silica gel (eluent: 80/20 DCM/MeOH). 40 mg of ethyl 1-((R)-3-(4-chlorophenyl)-2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}propionyl)-4-cyclohexylpiperidine-4-carboxylate in the form of a colourless oil are obtained in a yield of 15%.
Reaction SMILES: [OH:1][C:2]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:29])[CH:20]=[CH:21]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])([CH3:4])[CH3:3].[OH-:30].[K+].OO>C(O)C.O>[O:30]1[C@H:20]2[C:19](=[O:29])[CH:18]=[C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][C:2]([OH:1])([CH3:3])[CH3:4])[CH2:11][CH2:12]2)[CH:15]=[CH:16]3
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: [OH-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C

Procedure:
The trienone from (a) (1.3 gms) in ethanol (50 mls) was treated with 10% aqueous potassium hydroxide (0.5 ml) and 30% aqueous H2O2 (3 ml). After storage overnight at room temperature, the solution was diluted with water and the solid product collected. Recrystallization from aqueous methanol gave the title compound which after one further crystallization had melting point 162°-163°.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH3:13][N:14]([CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:1]([N:6]([CH3:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:2]
Reactant: CNCc1ccncc1
Reactant: CNc1ccccc1
Reactant: O=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(Cc1ccncc1)C(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Phosgene in toluene (50 ml, 121/2% solution was stirred at 0°-10° whilst a mixture of N-methylaniline (5.4 g) and triethylamine (15 ml) in dry chloroform (100 ml) was added slowly dropwise. On completion of the addition the mixture was stirred for 19 hours at room temperature, then cooled to 0°-10° whilst a solution of 4-(N-methylaminomethyl)pyridine (3.1 g) in dry chloroform (70 ml) was slowly added. The mixture was stirred at room temperature overnight followed by the cautious addition of 2 N hydrochloric acid (20 ml). After 1 hour, 5 N sodium hydroxide (12 ml) was added and the organic phase was separated, washed (H2O, 50 ml), dried (Na2CO3) and evaporated in vacuo to give a dark oil. The oil was dissolved in the minimum quantity of chloroform and chromatographed on a "Florisil" (Trademark) column eluted with chloroform. Appropriate fractions were identified by thin layer chromatography, combined and evaporated in vacuo to give 1,3-dimethyl-1-(4-pyridylmethyl)-3-phenylurea as a dark oil (3 g). The n.m.r. spectrum was compatible with the required structure.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[NH2:11][OH:12].C(O)C.Cl>O>[F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[C:5]([NH2:6])[O:12][N:11]=1
Reactant: N#CCC(=O)C(F)(F)F
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(C(F)(F)F)no1
Yield: 13.8 %

Procedure:
Trifluoroacetoacetonitrile (1.37 g, 0.010 mole), hydroxylamine hydrochloride (0.69 g, 0.010 mole), ethanol and water were heated under reflux for 3 hours. After the addition of hydrochloric acid (1.21 g, 0.012 mole), the mixture was further heated under reflux to give the title compound (0.21 g, 13.7%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12](=[O:15])[CH2:13][CH3:14].[CH2:16]=O.[OH-].[Na+]>C(O)(=O)C.O>[N:1]1([CH2:16][C:10]2[CH:9]=[C:8]([C:12](=[O:15])[CH2:13][CH3:14])[NH:7][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: C1COCCN1
Reactant: CCC(=O)c1ccc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCC(=O)c1cc(CN2CCOCC2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of morpholine (89.3 mmoles) in acetic acid (50 ml) at 0° C. there are added 1-(1H-pyrrol-2-yl)-propan-1-one (81.2 mmoles) and formaldehyde (89.3 mmoles) 37% in water. The reaction mixture is stirred overnight at ambient temperature. After concentration of the mixture, the solution is brought to alkaline pH (10-12) using 20% aqueous NaOH solution at 0° C. and is then extracted with DCM. The organic phase is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness and purified by flash chromatography on silica gel (SiO2; gradient 100% AcOEt to AcOEt/MeOH 9/1) to yield the title product.
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:27]=2)=[N:7][N:6]=1)(=O)=O.[N-:38]=[N+:39]=[N-:40].[Na+]>CS(C)=O.O>[N:38]([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[N:27]=2)=[N:7][N:6]=1)=[N+:39]=[N-:40]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(N=[N+]=[N-])s3)ccc21
Temperature: 60 °C
Yield: 85.9 %

Procedure:
To a solution of tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (300 mg, 0.554 mmol) in DMSO (3 mL) was added sodium azide (215.8 mg, 3.32 mmol). The reaction was heated at 55-65° C. for 4 h, then diluted with H2O and extracted with EtOAc (80 mL×3). The combined organic layers were washed with water (50 mL×4), dried, filtered and concentrated to give the crude material (240 mg). MS (ESI, pos. ion) m/z: 505 (M+1).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.CN1CCOCC1.[Cl:17][C:18]1[S:22][C:21]([C:23]([NH:25][C@H:26]2[CH2:30][N:29]([CH2:31][C:32](=[O:48])[NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]4=[O:46])=[CH:36][C:35]=3[F:47])[C@H:28]([C:49](O)=[O:50])[CH2:27]2)=[O:24])=[CH:20][CH:19]=1>COCCOC>[F:47][C:35]1[CH:36]=[C:37]([N:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]2=[O:46])[CH:38]=[CH:39][C:34]=1[NH:33][C:32]([CH2:31][N:29]1[C@H:28]([CH2:49][OH:50])[CH2:27][C@@H:26]([NH:25][C:23]([C:21]2[S:22][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:24])[CH2:30]1)=[O:48]
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CO)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 13.7 %

Procedure:
To a solution of 44 mg cyanuric chloride in 1.5 ml 1,2-dimethoxyethane were added 0.03 ml N-methylmorpholine. The resulting white suspension was treated with 150 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (example 12) in 0.5 ml 1,2-dimethoxyethane and stirred at r.t for 3 hrs. The precipitate was filtered off. The filtrate was cooled to 0° C. A solution of 13 mg NaBH4 in 0.7 ml H2O was added dropwise. The mixture was stirred for 5 min at 0° C., then diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtrated and concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 20 mg 5-chloro-thiophene-2-carboxylic acid ((3R,5S)-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-5-hydroxymethyl-pyrrolidin-3-yl)-amide. White solid. MS 505.4 ([M+H]+)