Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.[CH:27]([C:29]1[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=1)=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[C:37]([O:36][C:35](=[O:41])[NH:34][CH2:33][C:32]1[CH:31]=[CH:30][C:29]([C:27]2[NH:1][C:2]3=[N:3][CH:4]=[C:5]([Br:26])[C:6]([N:11]4[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:19])[NH:20][C:21]5[S:22][CH:23]=[CH:24][N:25]=5)[CH2:13][CH2:12]4)=[C:7]3[N:8]=2)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5nccs5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 35.5 %

Procedure:
To a mixture of 2-[4-(2-amino-5-bromo-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.1 g, 0.22 mmol) and ethanol (5 ml) was added tert-butyl N-(4 formylbenzyl)carbamate (69 mg, 0.29 mmol) and a freshly prepared aqueous solution of Na2S2O4 (1M; 900 μL, 0.9 mmol). The reaction mixture was stirred at 80° C. for 16 h then concentrated in vacuo. The crude product was purified by chromatography on silica gel (dichloromethane/ethyl acetate 7:3+0.5% methanol to 2% methanol in ethyl acetate). The isolated product was further triturated in ether/methanol 9:1, filtered, and dried in vacuo to give the title compound as a pale yellow solid (0.049 g, 34%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[F:23])=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2F)cc1
Yield: 69.4 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 2-fluorophenylboronic acid (0.026 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.048 g (69%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2′-fluorobiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16](=O)[CH2:17]Br)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.C(OCC)(=O)C>C1COCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[N:3]=[CH:1][S:2][CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: NC=S
Reactant: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1cc(-c2cscn2)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Freshly prepared thioformamide (Helv. Chim. Acta, 31, 2065, 1948) (160 mg) was added to a solution of α-bromoketone from Step 2 (200 mg) in THF (5 mL) and the reaction mixture was stirred at r.t. for 2 h. Ethyl acetate was then added and the organic phase was washed with saturated aqueous NH4Cl, H2O and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (65:35) afforded the title compound as a white solid.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: [N-]=[N+]=NC[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NC[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
To a solution of 20.9 g (64.5 mmol) of the azido compound obtained in Step B in 650 mL of THF, there are successively added 25.5 g (97.2 mmol) of triphenylphosphine and 157 mL of water. The batch is refluxed for 2 hours 30 minutes. The reaction mixture is then concentrated to dryness and the residue oil is then taken up in isopropyl ether. A white precipitate appears; it is filtered off and washed with isopropyl ether. The filtrate is then concentrated to dryness and then purified by chromatography over silica gel using dichloromethane and methanol as eluants. The title product is obtained in the form of an oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:25]=2[N:26]=1>>[CH3:17][N:18]([CH3:33])[CH2:19][CH2:20][N:21]([CH3:32])[C:22]1[S:23][C:24]2[CH:30]=[C:29]([NH:31][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:10][CH:9]=3)[CH:28]=[CH:27][C:25]=2[N:26]=1
Reactant: CN(C)CCN(C)c1nc2ccc(N)cc2s1
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C(Cl)C(=O)Cl
Product: CN(C)CCN(C)c1nc2ccc(NC(=O)c3ccc(I)cc3)cc2s1

Procedure:
The title compound is prepared by following Method C, using 4-iodo-benzoic acid (4.46 g, 17.97 mmol), oxalyl chloride (5.2 mL, 59.11 mmol) and N*2*-(2-dimethylamino-ethyl)-N*2*-methyl-benzothiazole-2,6-diamine (3.0 g, 11.98 mmol) to afford 3.77 g, 66%). LC/MS, Retention time=5.62 min; (m/z): calcd for C19H211N4OS: 480.4; found: 480.7.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:12])[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=1.[F:13][C:14]([F:18])([F:17])CO>>[CH3:12][C:5]1[C:6]([C:9]([OH:11])=[O:10])=[N:7][CH:8]=[C:3]([O:2][CH2:1][C:14]([F:18])([F:17])[F:13])[N:4]=1
Reactant: COc1cnc(C(=O)O)c(C)n1
Reactant: OCC(F)(F)F
Product: Cc1nc(OCC(F)(F)F)cnc1C(=O)O

Procedure:
The title compound was synthesized according to Intermediate 13, using 2,2,2,-trifluoroethanol (Aldrich) in Step 4. MS m/z=237 (M+H).
Reaction SMILES: Br.Br[CH2:3][CH2:4][NH2:5].COCCOC.Cl.[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:13]([NH:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]2[O:33][CH2:3][CH2:4][N:5]=2)=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Reactant: NCCBr
Agent: Br
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCCCCCCCC=CCCCNc1ccc(C2=NCCO2)cc1

Procedure:
To a slurry of 15 g. of 2-bromoethylamine hydrobromide in 150 ml. of 1,2-dimethoxyethane are added simultaneously solutions of 31 g. of 4-(4-tetradecenylamino)benzoyl chloride hydrochloride in 60 ml. of 1,2-dimethoxyethane and 50 cc. of triethylamine (dropwise). Upon addition of 0.5 g. of 4-dimethylaminopyridine the mixture is stirred at room temperature overnight. The solution is refluxed for one hour and filtered. The solid is oven dried and partitioned between methylene chloride and water. The layers are separated and the organic phase dried over magnesium sulfate. The organic layer is concentrated and the residue collected and crystallized from cyclohexane and recrystallized from acetonitrile to yield the product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C@H:6]2[O:12][C@H:11]([CH:13]=O)[C@@H:10]([OH:15])[C@H:9]([OH:16])[C@H:7]2[N:8]=1)[CH3:2].Cl.[CH3:18][NH:19][CH3:20].C([BH3-])#N.[Na+].CO.C(Cl)Cl>CO>[CH3:18][N:19]([CH2:13][C@H:11]1[O:12][C@H:6]2[C@H:7]([N:8]=[C:4]([NH:3][CH2:1][CH3:2])[S:5]2)[C@@H:9]([OH:16])[C@@H:10]1[OH:15])[CH3:20]
Reactant: CNC
Reactant: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](C=O)O[C@@H]2S1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCNC1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CN(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde (40.00 mg; 0.16 mmol; 1.00 eq.) in MeOH (1.00 ml) was added dimethylamine hydrochloride (15.89 mg; 0.19 mmol; 1.20 eq.), and sodium cyanoborohydride (5.10 mg; 0.08 mmol; 0.50 eq.) in 0.5 mL MeOH. The reaction was stirred at room temperature for 15 min. The desired product was isolated by flash chromatography (KPNH column, 0 to 100% MeOH/DCM, 15CV) to afford (3aR,5R,6S,7R,7aR)-5-[(dimethylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol (9.6 mg, 21%) as a white solid (once lyophilized).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=[O:5].[OH-:11].[Na+].Cl.[Cl-].[Na+]>CCCCCC.C(OCC)(=O)C>[OH:11][CH2:2][C:3]1[C:4]([O:6][C:7](=[O:10])[C:8]=1[CH3:9])=[O:5]
Reactant: [OH-]
Reactant: CC1=C(CBr)C(=O)OC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1=C(CO)C(=O)OC1=O
Reaction time: 12 h
Yield: 26 %

Procedure:
To 2-bromomethyl-3-methylmaleic anhydride (1.25 g, 6.10 mmol) was added 5 M aqueous sodium hydroxide solution (4 mL) at room temperature, and the mixture was stirred for 12 h. The reaction mixture was adjusted to pH 1 with 5 M hydrochloric acid (5 mL), added with sodium chloride and extracted three times with ethyl acetate. The combined organic layer was concentrated under reduced pressure, and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate 2:1) to give 227 mg of the title compound as oil (yield: 26%).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:10]3[CH:11]=[C:12]([S:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.C(N1C=CC([C:42](=[NH:44])[NH2:43])N1C(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:10]3[CH:11]=[C:12]([S:16][CH2:17][CH2:18][NH:19][C:42]([NH2:44])=[NH:43])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCC(OC(c2cccc(SCCN)c2)c2nc3cc(F)ccc3[nH]2)CC1
Reactant: CC(C)(C)OC(=O)N1C=CC(C(=N)N)N1C(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(OC(c2cccc(SCCNC(=N)N)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine (example 437B, 230 mg) in acetonitrile (15 mL) is added is added N,N′-bis-Boc-guanylpyrazole (172 mg) and diisopropylethylamine (1 equivalent) at room temperature. The mixture is stirred at room temperature for 3 h. The solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol from 100/0 to 95/5). The residue is then dissolved in 5N aqueous hydrochloric acid (8 mL) and the solution is stirred overnight at room temperature. The solvent and volatiles are removed under reduced pressure and the residue is triturated with diethyl ether and filtered to afford N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl) guanidine trihydrochlorhide as a white crystalline solid melting at 170° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]1[S:14][CH:15]=[C:16]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=3[CH:22]=2)[N:17]=1)[C:6]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)=[O:7].C(N(CC)C(C)C)(C)C.[C:36]([N:39]1[CH2:47][CH2:46][CH:42]([C:43](Cl)=[O:44])[CH2:41][CH2:40]1)(=[O:38])[CH3:37]>C(Cl)(Cl)Cl>[C:36]([N:39]1[CH2:40][CH2:41][CH:42]([C:43]([NH:1][CH2:2][CH2:3][CH2:4][N:5]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[O:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[CH:22]=3)[N:17]=2)[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[O:7])=[O:44])[CH2:46][CH2:47]1)(=[O:38])[CH3:37]
Reactant: NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)NCCCN(C(=O)c2cccs2)c2nc(-c3cc4ccccc4o3)cs2)CC1
Temperature: 25 °C

Procedure:
A mixture of the amine prepared above (77 mg, 0.2 mmol) and N,N-diisopropylethylamine (139 μL, 0.8 mmol) was dissolved in chloroform (2 mL), and a portion of the solution (200 μL, 0.02 mmol) was added to a solution of 1-acetyl-isonipecotoyl chloride (7.6 mg, 0.04 mmol) in chloroform (200 μL). The reaction mixture was maintained at room temperature overnight.). The reaction mixture was maintained at room temperature overnight, then concentrated in vacuo. The resulting residue was dissolved in DMSO (200 μL) and subjected to HPLC purification (Method Z) to provide the title compound (4.5 mg) as a yellowish solid. LC/MS (ESI) m/z 537.1 [M+H]. HPLC retention time (Method C)=3.44 min.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH3:5].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32]I)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][CH2:32][C:6]([CH2:3][CH2:4][CH3:5])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ICCc1ccccc1OCc1ccccc1
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CCc1ccccc1OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a suspension of sodium hydride (1.3 g) in dimethylformamide (15 ml), a solution of diethyl propylmalonate (6.6 g) in dimethylformamide (45 ml) was added under ice-cooling and the mixture was stirred at room temperature for an hour. To the solution was added a solution of 2-(2-benzyloxyphenyl)ethyl iodide (10 g) in dimethylformamide (30 ml), the mixture was stirred at the same temperature for an hour and left standing overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydrogencarbonate solution and a saturated brine and dried over magnesium sulfate. The solvent was distilled away under reduced pressure and the residue was subjected to silica gel chromatography (eluent; hexane-ethyl acetate=8:1) to give the subject compound (10 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.[CH3:10]O>>[CH3:10][O:8][C:7]([C@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1)=[O:9]
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: CO
Product: COC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 0 °C
Yield: 95 %

Procedure:
Cis-4-Hydroxy-D-proline (15 g, 115 mmol) was suspended in 150 mL anhydrous methanol under an argon atmosphere, then cooled to 0° C. before bubbling in HCl gas for 15 minutes. The solution gradually became homogenous. The argon and HCl gas lines were removed and the solution was refluxed for 4 h. The solution was cooled and then concentrated under reduced pressure. The crude material was redissolved in 100 mL methanol and diethyl ether was added until a precipitate formed. The precipitate was filtered off, washed with diethyl ether, and dried in vacuo overnight to give 1 (20 g, 95%) as a white solid. MS: APCI (AP+): 146 (M)+.
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[CH2:27]([N:34]1[CH2:38][C@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)[C@@H:36]([CH:47]=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:35][C@H:36]([CH:47]=[CH2:2])[C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=2)[CH2:38]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Reaction time: 1 h
Yield: 61.7 %

Procedure:
To a suspension of methyltriphenylphosphonium iodide (6.35 g, 15.6 mmol) in THF (60 mL) was added n-BuLi (1.6N in heptane, 7.4 mL, 0.0119 mol) dropwise at 0° C. and stirred for one hour. To this reaction mixture was added a solution of (3R,4S)-1-benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carbaldehyde 2.77 g (9.2 mmol) in THF (15 mL) dropwise at 0° C. and stirred for another one hour. The reaction was quenched by aq. ammonium chloride solution and extracted with ethylacetate. The separated organic layer was dired on anhydrous sodium sulfate and concentrated in vaccuo. The residue was purified by silica gel column chromatography eluted by a mixture of heptane and ethyl acetate (7:3) yielding 1.7 g (62%) of the title compound as a light yellow oil ES-MS m/e: 300.1 (M+H+).
Reaction SMILES: C(O)(=O)C.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]2[C:23]3[N:22]4[CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]([NH2:27])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:6]=1.[NH:28]1[C:32]2[N:33]=[CH:34][CH:35]=[C:36]([C:37](O)=[O:38])[C:31]=2[CH:30]=[CH:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]2[C:23]3[N:22]4[CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]([NH:27][C:37]([C:36]4[C:31]5[CH:30]=[CH:29][NH:28][C:32]=5[N:33]=[CH:34][CH:35]=4)=[O:38])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:6]=1
Reactant: NC1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21
Reactant: O=C(O)c1ccnc2[nH]ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(NC1c2cccc(-c3cnc4ccccc4c3)c2-n2cccc21)c1ccnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
In a 100 ml round-bottomed flask under argon, a mixture of 116 mg of 5-quinolin-3-yl-9H-pyrrolo[1,2-a]indol-9-ylamine acetate obtained according to the preceding stage, 63 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (which can be obtained according to WO 2003/000688), 82 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 58 mg of 1-hydroxybenzotriazole (HOBt) in 7.5 ml of dimethylformamide is stirred at ambient temperature for 18 hours. The reaction medium is evaporated to dryness under vacuum, 50 ml of water are added to the residue, and the suspension is stirred for 1 hour. The solid is filtered and washed with water, then with a saturated solution of sodium bicarbonate and again with water. The resulting product is spin-filter-dried overnight and then the solid is taken up in a mixture of methanol and dichloromethane (10/90 v/v), and the solvent is evaporated to dryness under vacuum. The residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of methanol and dichloromethane (3/97 v/v). 53 mg of 1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid (5-quinolin-3-yl-9H-pyrrolo[1,2-a]indol-9-yl)amide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CN(C)C(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[N:3][CH:2]=1
Reactant: Nc1ccncn1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of pyrimidine-4-amine (1.00 g, 10.5 mmol) and pyridine (2.55 ml, 31.5 mmol) in N,N-dimethylacetamide (50 ml) was added 2,2,2-trichloroethyl chloroformate (2.55 ml, 31.5 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (1.97 g, 69.4%) as a solid was collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[CH:8]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[CH:8]=[CH:11][C:12](=[O:13])[CH:14]=[CH:8][C:7]1[CH:6]=[CH:5][C:4]([CH3:10])=[CH:3][C:2]=1[Cl:1]
Reactant: CC(C)=O
Reactant: Cc1ccc(C=O)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2Cl)c(Cl)c1

Procedure:
The starting material, 1,5-bis(3-chloro-p-tolyl)-1,4-pentadien-3-one is prepared by the reaction of two moles of 3-chloro-p-tolualdehyde [Wahl, Ann. Chim. [11] 5 (1936), pp. 5, 39] and one mole of acetone in ethanol solution in the presence of sodium hydroxide.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10](OC(C)(C)C)=O)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20])=[O:4].Cl.[C:29]1(B(O)O)[CH:34]=[CH:33]C=[CH:31][CH:30]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][N:8]([C:10]2[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=2)[CH2:7][N:6]1[C:17](=[O:27])[CH:18]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]([CH3:20])[CH3:21])=[O:4]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)OC(C)(C)C)CC1C(=O)OC)C(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CN(c2ccccc2)CC1C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.2 %

Procedure:
3-(2-Methoxycarbonylamino-3-methyl-butyryl)-imidazolidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (0.20 g, 0.515 mmol) was dissolved in dichloromethane (1.0 mL) and HCl (4M dioxane, 1 mL) was added. The resultant suspension was stirred at room temperature for 60 minutes, after which all volatiles were removed in vacuo. The crude material was combined with phenyl boronic acid (188 mg, 1.545 mmol) and DCM (15 mL) was added. Triethylamine (1.2 mL, 8.89 mmol) was added, followed by copper(II) acetate and molecular sieves 4 Å. The reaction was stirred at room temperature. After 24 hrs, the reaction was quenched with aqueous ammonium hydroxide solution (10%) and the organic layer was isolated. The organic layer was washed with aqueous HCl solution (0.5 M), brine, and was dried over sodium sulfate. Filtration and evaporation gave crude material. Purification via flash chromatography on silica gel (eluent: EtOAc/hexanes) yielded the desired product 3-(2-Methoxycarbonylamino-3-methyl-butyryl)-1-phenyl-imidazolidine-4-carboxylic acid methyl ester (51.0 mg, 0.14 mmol): LCMS-ESI+: calc'd for C18H25N3O5: 363.4 (M+). Found: 364.4 (M+H+).