Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:13]2[CH:14]=[C:15]([N:19]3[CH2:28][C:27]4[CH:26]=[N:25][CH:24]=[C:23]([C:29](O)=[O:30])[C:22]=4[CH2:21][CH2:20]3)[CH:16]=[CH:17][CH:18]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.CCCP(=O)=O.[NH2:45][CH2:46][CH2:47][CH2:48][OH:49]>CN(C1C=CN=CC=1)C.ClCCCl>[OH:49][CH2:48][CH2:47][CH2:46][NH:45][C:29]([C:23]1[C:22]2[CH2:21][CH2:20][N:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][C:6]4[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)=[O:12])[CH:14]=3)[CH2:28][C:27]=2[CH:26]=[N:25][CH:24]=1)=[O:30]
Reactant: NCCCO
Reactant: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)O)C3)c2)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4c(cncc4C(=O)NCCCO)C3)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.5 %

Procedure:
To a mixture of 7-(3-{[(3-isopropylphenyl)amino]carbonyl}phenyl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carboxylic acid (47 mg, 0.113 mmol), triethylamine (0.047 mL, 0.34 mmol), and catalytic DMAP in 3.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.081 mL, 0.136 mmol). After 5 min at rt, 3-amino-1-propanol (0.011 mL, 0.147 mmol) was added and the reaction stirred at rt for 2 hours. The reaction was quenched with aqueous NaHCO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, aqueous NaHCO3 solution, brine, dried with anhydrous Na2SO4 and rotary evaporated. This material was chromatographed eluting with CHCl3/EtOAc plus 10% MeOH to give the title compound as a light yellow solid (20 mg, 37%). 1H NMR (CDCl3) δ: 8.46 (s, 1H), 8.41 (s, 1H), 8.02 (s, 1H), 7.54 (s, 1H), 7.44-7.51 (m, 2H), 7.19-7.39 (m, 4H), 7.10 (d, J=8.2 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 6.81 (t, J=5.6 Hz, 1H), 4.45 (s, 2H), 3.78 (t, J=5.4 Hz, 2H), 3.53-3.65 (m, 4H), 3.17 (t, J=5.6 Hz, 2H), 2.86-2.97 (m, 1H), 1.77-1.86 (m, 2H), 1.27 (d, J=6.7 Hz, 6H)
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9]>>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNCCCC
Reactant: ClCC1CO1
Product: CCCCN(CCCC)CC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.2 %

Procedure:
A stirred solution of epichlorohydrin (20.0 g, 0.22 mole) is treated dropwise with di-n-butylamine (29.73 g, 0.23 mole) over a 1 hour period followed by continued stirring at room temperature overnight. The reaction mixture is washed with 20% K2CO3 (50 ml). The organic layer is then stirred with 40% NaOH for 1 hour and then extracted with 3×100 ml portions of ether. The etheral extracts are pooled and washed with H2O (100 ml). The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to leave the crude product (I) weighing 39.42 g. The crude product is distilled at 52°/0.15 mmHg to give 8.24 g (20.2%) pure product to be used as an intermediate in Part B.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:13]2[CH:22]=[C:21]3[C:16]([C:17]([CH3:27])([CH3:26])[CH2:18][CH2:19][N:20]3[CH:23]([CH3:25])[CH3:24])=[CH:15][C:14]=2[CH3:28])[CH3:12])=[CH:7][CH:6]=1)C.[OH-].[K+]>C(O)C>[CH:23]([N:20]1[C:21]2[C:16](=[CH:15][C:14]([CH3:28])=[C:13]([N:11]([CH3:12])[C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:29])=[O:3])=[CH:10][CH:9]=3)[CH:22]=2)[C:17]([CH3:27])([CH3:26])[CH2:18][CH2:19]1)([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)(C)CCN3C(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(cc1N(C)c1ccc(C(=O)O)cc1)N(C(C)C)CCC2(C)C
Temperature: 50 °C
Reaction time: 18 h
Yield: 84.7 %

Procedure:
A solution of 4-[(1-isopropyl-4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-methyl-amino]-benzoic acid ethyl ester (Compound 47, 8.9 mg, 0.02256 mmol) in ethanol (1 mL) was treated with 2N KOH (0.5 mL) and stirred at 50° C. for 18 hours. The solvent was removed under reduced pressure and the residue was washed with ethyl acetate and acidified with 2N HCl. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (50% ethyl acetate in hexane, Rf=0.22) to give the title compound (7 mg, 85%) as a white solid:
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([C:15](Cl)=[O:16])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[NH:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:18]1[C:28]2[CH2:27][CH2:26][C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[N:23]([C:15]([CH:12]3[CH2:13][CH2:14][N:9]([CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:10][CH2:11]3)=[O:16])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Reactant: O=C(Cl)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Product: O=C(C1CCN(Cc2ccccc2)CC1)N1c2ccccc2CCc2ccccc21
Reaction time: 14 h
Yield: 36.4 %

Procedure:
A mixture of 1-benzyl-4-piperidinecarbonylchloride hydrochloride (25.0 g, 91 mmol), 10,11-dihydro-5H-dibenzo[b,f]azepine (17.6 g, 90 mmol), N,N-dimethylaniline (25 ml) and toluene (150 ml) was heated at reflux temperature under stirring for 14 h. The mixture was decanted and to the remaining solid 10% ammonia (100 ml) and chloroform (150 ml) were added. The phases were separated and the combined toluene and chloroform phases were dried (K2CO3) and evaporated in vacuo. The residue was purified by chromatography on silica gel (300 g) using benzene and ethyl acetate as eluents. The crude base was crystallised from cyclohexane, yielding 13.0 g (36%) of 4-((10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)carbonyl)-1-benzylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=O)[NH:7][C:6]=2[CH:17]=1.[CH3:18][CH:19]1[CH2:24][NH:23][CH2:22][CH2:21][NH:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:23]3[CH2:22][CH2:21][NH:20][CH:19]([CH3:18])[CH2:24]3)=[N:7][C:6]=2[CH:17]=1
Reactant: CC1CNCCN1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Product: CC1CN(C2=Nc3cc(Cl)ccc3Nc3ccccc32)CCN1
Yield: 91.8 %

Procedure:
8-Chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepine-11-one (25 mg, 0.1 mmol) and 2-methylpiperazine (100 mg, 1.0 mmol) were reacted according to GP4 to give 30 mg of the title compound (160FE38). MS (ESI) 327 (MH+). Purity for MH+ (UV/MS) 100/89.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][N:12]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([CH3:30])[N:21]=1)[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>C(Cl)Cl>[CH3:11][N:12]([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[C:22]([CH3:30])[N:21]=1)[C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH:1]=[O:3])=[CH:17][CH:18]=1
Reactant: O=CO
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: Cc1nc(N(C)c2ccc(NC=O)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
To a solution of formic acid 1 mL and acetic anhydride 1 mL, stirred at room temperature for 1 h, was added a solution of N-methyl-N-(2-methylquinazolin-4-yl)benzene-1,4-diamine 0.132 g (0.5 mmol) in CH2Cl2 5 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. After concentration, the crude product was purified by recrystallization in EtOAc/MeOH to give the titled compound in 85% yield. The compound was further purified with preparative HPLC for analytical uses. 1H NMR (CD3OD, 400 MHz): δ 7.84-7.79 (m, 2H), 7.71-7.65 (m, 1H), 7.44-7.41 (m, 1H), 7.27-7.28 (m, 2H), 7.02-6.99 (m, 2H), [3.84 (s, 1H), 3.81 (s, 2H)], [2.78 (s, 1H), 2.76 (s, 2H)] (Two isomers were observed in 2:1 ratio.). m/e: 293.1438 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[C:14]3[C:13]([C:24]([CH2:27][OH:28])([CH3:26])[CH3:25])=[N:12][NH:11][C:10]=3[C:9]2=[O:29])=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[OH:28][CH2:27][C:24]([C:13]1[C:14]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[CH:7][CH:6]=3)[C:9](=[O:29])[C:10]=2[NH:11][N:12]=1)([CH3:25])[CH3:26]
Reactant: OB(O)c1ccsc1
Reactant: COc1ccccc1C1c2c(C(C)(C)CO)n[nH]c2C(=O)N1c1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccccc1C1c2c(C(C)(C)CO)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 25.1 %

Procedure:
A mixture of 5-(4-bromophenyl)-3-(1-hydroxymethyl-1-methylethyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.15 g, 0.33 mmol), thiophene-3-yl boronic acid (0.063. g, 0.49 mmol), tripotassium phosphate (0.21 mg, 0.99 mmol), 1,2-Dimethoxyethane (3 mL) and water (0.6 mL) was placed in a flask under nitrogen. To the mixture was added 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.027 mg, 0.033 mmol) and the resulting mixture was heated at reflux for 5 hours. After the reaction was completed, the reaction mixture was purified on a silica gel column chromatography (ethyl acetate/n-hexane). The resulting aimed compound was triturated with ethyl acetate and n-hexane to give 3-(1-hydroxymethyl-1-methylethyl)-4-(2-methoxyphenyl)-5-(4-thiophene-3-ylphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.038 g, yield: 25%) as colorless solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([CH:10]=[CH:11][C:12](O)=[O:13])[CH:7]=2)[O:2]1>CN(C=O)C.C(O)C.Cl.[Pd]>[CH2:1]1[O:2][C:3]2[CH:4]=[C:5]3[C:6]([CH2:10][CH2:11][C:12](=[O:13])[NH:15]3)=[CH:7][C:8]=2[O:9]1
Reactant: O=C(O)C=Cc1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1CCc2cc3c(cc2N1)OCO3
Yield: 80.9 %

Procedure:
3-(4,5-methylenedioxy-2-nitrophenyl)acrylic acid (10 g, 42 mmol) in 50 ml dry DMF, 450 ml absolute ethanol and 1.5 ml conc. HCl was reduced catalytically at 1 atm., 22° C., using 1.5 g 5% palladium on carbon to give 6.5 g 6,7-methylenedioxy-1,2,3,4-tetrahydro-2-oxoquinoline as light brown crystals, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1c(F)cccc1Cl
Agent: Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 2-chloro-6-fluorobenzaldehyde oxime (5.13 g, 29.6 mmol) in DMF (50 ml) was added a portion of N-chlorosuccinimide followed by a syringe of HCl gas (5 ml from the vapors of a conc. HCl solution). The temperature increased slightly and the rest of the N-chlorosuccinimide (total of 4.07 g, 30.5 mmol) was added. After stirring at room temperature for 1 h, ice was added and the mixture was extracted twice with diethyl ether. The combined organic fractions were washed (brine), dried (MgSO4), filtered, and concentrated. Column chromatography (silica gel, hexane/Et2O gradient) gave 2-chloro-6-fluorobenzoylchloride oxime (4.83 g, 78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH2:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:29])=[O:28]>COCCOC.CCO.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>[C:1]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][C:27]([OH:29])=[O:28])[CH:33]=1)[CH3:9])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(CCC(=O)O)c1
Temperature: 160 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3122 μmol) in a mixture of DME/EtOH/2N Na2CO3: 1/1/1 (20 ml) were added 3-carboxyethylphenylboronic acid (1.5 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 160° C. for 15 minutes. The reaction mixture was cooled to RT, filtered over celite and washed with EtOAc and MeOH. The solvents were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][N:17]([CH3:36])[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:27]=2)[CH:22]=[CH:21]1)=[O:19]>C(Cl)Cl>[CH3:16][N:17]([CH3:36])[C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH:27]=2)[C:22]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)=[CH:21]1)=[O:19]
Reactant: CN(C)C(=O)n1ccc2ccc(-c3ccc(F)cc3)cc21
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)C(=O)n1cc(C(=O)c2ccc(CCl)cc2)c2ccc(-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a solution of 4-(chloromethyl)benzoyl chloride (804 mg, 4.26 mmol) in CH2Cl2 (21 mL) was added AlCl3 (850 mg, 6.39 mmol) in a single portion, and the yellow solution was stirred for 15 min at ambient temperature. A solution of 6-(4-fluorophenyl)indole-1-carboxylic acid dimethylamide (1.00 g, 3.55 mmol), prepared as in step 1, in CH2Cl2 was added dropwise and the dark solution was stirred for 2 hours at ambient temperature. Additional AlCl3 (0.24 g, 1.78 mmol) was added and the reaction mixture was stirred for 0.5 hours. The reaction mixture was poured into a separatory funnel containing ice water and CH2Cl2. The layers were separated and the aqueous phase was extracted three times with CH2Cl2. The combined organic layers were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated in vacuo. Pure 6-(4-fluorophenyl)-3-(4 -chloromethylbenzoyl)indole-1-carboxylic acid dimethylamide (294 mg) was obtained by chromatography on silica gel (25%, then 50% ethyl acetate/hexanes).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH4+:18].[OH-].C([O-])([O-])=O.[K+].[K+]>>[CH3:8][C:6]1[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]2=[C:2]([NH2:18])[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: [NH4+]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(N)c2nc(-c3ccccc3)cc-2[nH]1
Yield: 5.4 %

Procedure:
This compound was prepared according to the method described in Example 26 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (0.10 g, 0.41 mmol) with NH4OH (Aldrich Chemical Company) (2.5 mL, 21.4 mmol) and K2CO3 (0.33 g, 2.4 mmol). The crude reaction mixture was concentrated to dryness and the residue extracted with hot MeOH and concentrated. The resulting yellow oil was purified by flash chromatography on silica gel (1:40 MeOH/CH2Cl2 followed by 1:20 MeOH/CH2Cl2) to give 0.005 g (5%) of the title compound as an off-white solid. Mp: >280° C. 1H NMR (CD3OD; 500 MHz): δ 2.53 (s, 3), 6.74 (s, 1), 7.44 (t, 1, J=7.2), 7.52 (t, 2, J=7.5), 7.82 (d, 2, J=7.5); MS m/z: 225 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=1)=O)(C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH:20]([C:16]1[CH:15]=[C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)[CH:19]=[CH:18][CH:17]=1)=[CH2:21]
Reactant: C=Cc1cccc(C2CCCCN2C(=O)OC(C)(C)C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=Cc1cccc(C2CCCCN2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-(3-vinyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (650 mg, 2.26 mmol) in dichloromethane (15 mL) was cooled to 0° C., before adding trimethylsilyl trifluoromethanesulfonate (569 μL, 3.39 mmol). The reaction mixture was stirred at 0° C. for 1 h before adding N,N-diisopropylethylamine (1.6 mL, 5.24 mmol) to afford the 2-(3-vinyl-phenyl)-piperidine as a yellow solid. The solid was redissolved, along with 28f (900 mg, 1.98 mmol) in acetonitrile (20 mL). The solution was cooled to 0° C., before adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.05 g, 2.77 mmol) and N,N-diisopropylethylamine (1.4 mL, 7.92 mmol). The stirred reaction mixture was allowed to slowly warm to RT. After 2 h, the solvent was evaporated and the remaining residue dissolved in ethyl acetate (30 mL) and washed with water (3×30 mL). The organics were dried over anhydrous sodium sulfate, filtered and concentrated. The resultant residue was purified by silica gel chromatography using a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 0:1 to afford the title compound (1.25 g, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[N:11](S(C3C=CC=CC=3)(=O)=O)[C:8]2=[N:9][CH:10]=1)=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[CH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:11][C:8]2=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)nc1)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc2[nH]c(C(=CC3CCCC3)c3ccc(S(C)(=O)=O)nc3)cc2c1
Yield: 86 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (230 mg, 0.41 mmol) and a tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 3.2 mL) was stirred at 25° C. for 16 h. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous ammonium chloride solution (4×100 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(6-methanesulfonyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-carboxylic acid methyl ester (150 mg, 86%) which was used in the next step without further purification: LC/MS m/e calcd for C22H23N3O4S [M+H]+ 426.51, observed 426.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[C:42][CH:43]=[C:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[N:36]=1>C(Cl)Cl.CN(C=O)C>[CH3:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[C:42][CH:43]=[C:44]2[CH2:45][CH2:46][N:47]([C:6](=[O:8])[C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:48][CH2:49]2)[N:36]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cccc(C#CC=C2CCN(C(=O)c3ccccc3[N+](=O)[O-])CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution 2-nitrobenzoic acid (42.6 mg, 0.25 mmol) in CH2Cl2 (2 mL) and DMF (0.5 mL) stirred at 0-5° C., was added 1-hydroxybenzotriazole (50 mg, 0.322 mmol) and, after 30′, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (62 mg, 0.323 mmol). Afterwards, the Compound of Example 3 (53 mg, 0.25 mmol) was added. The reaction mixture was stirred at r.t. for 2 h and kept overnight at the same temperature. After dilution with water and 1 N NaOH, the organic layer was separated and washed with water, dried over Na2SO4 and evaporated to dryness in vacuo. Purification by flash chromatography (CHCl3-1.4 N MeOH/NH3 100:0.1) yielded the title compound (82 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[C:9]([O:13][C:14]([CH:16]([C:28](=[O:30])[CH3:29])[CH:17]([CH:23]([O:26][CH3:27])[O:24][CH3:25])[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:15])([CH3:12])([CH3:11])[CH3:10].[C:31](Br)#[C:32][CH2:33][CH2:34][CH3:35]>CC(C)=O>[C:28]([C:16]([C:14]([O:13][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:15])([CH2:31][C:32]#[C:33][CH2:34][CH3:35])[CH:17]([CH:23]([O:24][CH3:25])[O:26][CH3:27])[CH2:18][C:19]([O:21][CH3:22])=[O:20])(=[O:30])[CH3:29]
Reactant: CCCC#CBr
Reactant: COC(=O)CC(C(OC)OC)C(C(C)=O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC#CCC(C(C)=O)(C(=O)OC(C)(C)C)C(CC(=O)OC)C(OC)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 1.38 g quantity of potassium carbonate and 308 mg of potassium iodide are placed into a reactor. Acetone (30 ml) and a solution of 450 mg of methyl 4-tert-butoxycarbonyl-3-dimethoxymethyl-5-oxohexanoate in 10 ml of acetone are further placed into the reactor. Subsequently 270 mg of pentynyl bromide is added to the mixture. The resulting mixture is stirred at room temperature for one hour and thereafter refluxed at 70° C. for 13 hours. On completion of the reaction, the mixture is cooled to room temperature, and the solids are separated off. The product is concentrated in a vacuum, and the residue purified by a silica gel column, giving methyl 4-acetyl-4-tert-butoxycarbonyl-3-dimethoxymethyl-6-nonynoate (compound (8), R1 =t-Bu, R2 =R3 =CH3) in a yield of 91%.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].[Br:11]Br>O>[Br:11][C:8]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][CH:7]=1
Reactant: CC(C)c1cc[nH]n1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
1.10 g of 3-i-propyl-1H-pyrazole was suspended in 20 ml of water, and 1.6 g of 50% aqueous solution of sodium hydroxide was added to it. The mixture was cooled to 0° C., and then 1.76 g of bromine was added to the mixture, followed by stirring at room temperature for 5 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.88 g of 4-bromo-3-i-propyl-1H-pyrazole.