Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[NH:20][C:19](=S)[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[NH3:25]>>[Br:1][C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[N:20]=[C:19]([NH2:25])[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1
Reactant: N
Reactant: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(=S)N3)CC1
Product: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(N)=N3)CC1
Temperature: 120 °C

Procedure:
(7′-Bromo-4-methoxy-5″-methyl-3′,4′-dihydrodispiro[cyclohexane-1,2′-naphthalene-1′,2″-imidazole]-4″(3″H)-thione (Intermediate 15, 0.191 g, 0.47 mmol) and ammonia (7M in MeOH, 2.5 mL, 17.5 mmol) were mixed in a microwave vial. The vial was sealed and the reaction was heated at 120° C. for 30 min in a microwave reactor. The mixture was concentrated and the residue was dissolved in ammonia (7M in MeOH, 2.5 mL, 17.5 mmol) and heated at 120° C. for 30 min in a microwave reactor. This was repeated six more times (8 runs in total). After evaporation of the solvent, the residue was partitioned between DCM and 2 M citric acid. The phases were separated and the organic layer was extracted with 2 M citric acid. The organic layer was discarded while the combined aqueous phases were basified to ˜pH 12 by addition of 50% aq. NaOH. The aqueous phase was then extracted with EtOAc three times. The combined organic layers were dried using a phase separator and concentrated. The product was purified by preparative HPLC to give two isomers:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][C:18]1([C:23](Cl)=[O:24])[CH2:20][C:19]1([F:22])[F:21]>[Cu]Br.C1(C)C=CC=CC=1>[F:21][C:19]1([F:22])[CH2:20][C:18]1([C:23]([C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:24])[CH3:17]
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC1(C(=O)Cl)CC1(F)F
Agent: [Cu]Br
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C(=O)C#Cc2ccc(Cl)cc2)CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
13.7 g (0.1 mol) of p-chlorophenyl-acetylene are added to a mixture of 10.1 g (0.1 mol) of triethylamine, 1.4 g (0.01 mol) of copper(I) bromide and 55 ml of toluene, and the mixture is stirred for 30 minutes at room temperature under argon. After the reaction mixture has been heated to 55° C., 15.5 g (0.1 mol) of 1-methyl-2,2-difluorocyclopropanecarbonyl chloride are added dropwise. After this, the mixture is stirred for 8 hours at 90° C., and then cooled and filtered. The filtrate is washed with dilute aqueous hydrochloric acid and water in succession and concentrated under reduced pressure. 19.2 g of a dark oil remain which is distilled using a bulb tube. A yellow oil, which solidifies on standing, distils over at 0.1 mbar and a jacket temperature of 120° C. 8.4 g (33% of theory) of 2-(4-chlorophenyl)-ethin-1-yl 2,2-difluoro-1-methyl-cycloprop-1-yl ketone of melting point 67°-68° C. are obtained. ##STR54##
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH:3]=1.[CH3:10][CH2:11]O>O=S(Cl)Cl>[CH2:10]([O:8][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9])[CH3:11]
Reactant: CCO
Reactant: O=C(O)c1csc(Br)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1csc(Br)c1

Procedure:
A solution of 5-bromo-thiophene-3-carboxylic acid (14.5 g, 70 mmol) was dissolved in SOCl2 and the mixture was refluxed for 2 hours. The mixture was concentrated under reduced pressure to give a yellow oil. The oil was was dissolved in EtOH and the mixture was refluxed for 1 hour, then concentrated under reduced pressure to give 5-bromo-thiophene-3-carboxylic acid ethyl ester as an oil (16.46 g, quantitative).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH:36](O)[CH3:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:36]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[Cl:29])[CH3:37])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(O)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1Cl

Procedure:
In a similar manner as described for example B31, 8.9 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate, 5.0 g of 1-(2-chlorophenyl)ethanol, 11.2 g of triphenylphosphine (polymer bound, ˜3 mmol/g) and 9.8 g of di-tert-butyl azodicarboxylate in 260 ml anhydrous dichloromethane yield the title compound.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH:17]1([CH2:22][C:23](O)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:22][C:23]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)CC1CCCC1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(CC1CCCC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
The product of Example 11B and 2-cyclopentylacetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56-11.57 (m, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.11-8.17 (m, 1H), 8.04-8.08 (m, 1H), 8.00-8.05 (m, 1H), 2.34 (d, J=7.4 Hz, 2H), 2.16-2.28 (m, 1H), 1.77-1.86 (m, 2H), 1.57-1.66 (m, 2H), 1.48-1.57 (m, 2H), 1.21-1.32 (m, 2H); MS (ESI) m/z 340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.CN(CCN(C)C)C.[Li]C(CC)C.[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28](OC)=[O:29]>C1COCC1.C1(C)C=CC=CC=1>[F:25][C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([C:10]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8])=[O:29]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COC(=O)c1ccccc1F
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)O)c(C(=O)c2ccccc2F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
4-(Methoxy)benzoic acid (5.00 g, 32.9 mmol) was azeotroped with toluene thrice, then dissolved in 80 mL of dry THF. TMEDA (10.9 mL, 72.3 mmol) was added, and the mixture was cooled to −78° C. sec-BuLi (51.6 mL of 1.40 M in cyclohexane, 72.3 mmol) was added dropwise over a period of 30 minutes, and the solution was stirred for 15 minutes. Methyl 2-fluorobenzoate (5.02 mL, 39.4 mmol) was added in 1 portion and, after stirring for 15 minutes, the reaction was quenched with 20 mL of water. The mixture was warmed to ambient temperature and poured into 1.5 L of water. 30 mL 1N NaOH was added and the aqueous layer was extracted 1× with EtOAc; after which the organic layer was discarded. The aqueous layer was acidified with conc. HCl until pH=1 and then extracted 2× with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash chomatography through SiO2 (40-100% EtOAc/hexane) to provide the desired product (4.72 g, 52% yield) as a white solid. ESI+MS: 275.2 [M+H+].
Reaction SMILES: C(O[C:6](=[O:30])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:27][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH3:29])[N:24]=4)[N:19]=[CH:18][C:17]=3[NH:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[O:31]=[C:32]1[NH:37][C:36]2[CH:38]=[C:39](C(O)=O)[CH:40]=[CH:41][C:35]=2[S:34][CH2:33]1>>[CH3:29][O:28][C:23]1[N:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][C:17]1[NH:16][CH2:15][CH:14]([C@H:11]3[CH2:12][CH2:13][C@H:8]([NH:7][C:6]([C:39]4[CH:40]=[CH:41][C:35]5[S:34][CH2:33][C:32](=[O:31])[NH:37][C:36]=5[CH:38]=4)=[O:30])[CH2:9][CH2:10]3)[CH2:27][C:26]2=1
Reactant: COc1ccc2ncc3c(c2n1)CC([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CN3
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Product: COc1ccc2ncc3c(c2n1)CC([C@H]1CC[C@H](NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CN3

Procedure:
The titled compound is prepared as an off-white lyophilizated powder following Scheme 8 and in analogy to Example 1 using [trans-4-(6-methoxy-1,2,3,4-tetrahydro-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[NH2:7][C:8]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[CH:11]=[CH:10][CH:9]=[C:8]2[N:7]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(N)cccc12
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc2c(N3CCCC3)cccc12

Procedure:
1,4-Dibromobutane (220 g) is added dropwise to a stirred suspension of 1-amino-5-methoxynaphthalene (170 g) and sodium carbonate (200 g) in THF (300 ml), while maintaining the reaction temperature at less than 10° C. When the addition is complete, the stirred mixture is allowed to reach RT and refluxed overnight.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c(N)cccc1F
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N)cccc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
To a solution of cyclohexanol (19.1 g, 0.191 mol) in anhydrous THF (500 mL) was added NaH (7.6 g, 40% in mineral oil, 0.191 mol) in small portions at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 h and a solution of 2-amino-6-fluorobenzonitrile (20.0 g, 0.15 mol) in anhydrous THF (150 mL) was added drop-wise at room temperature. The reaction mixture was heated to reflux overnight then cooled to room temperature and most of the THF removed under reduced pressure. Ice water (100 mL) was added to the concentrated reaction mixture followed by EtOAc (500 mL). The organic layer was separated and successively washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with 25-30% EtOAc in hexanes to give 2-amino-6-(cyclohexyloxy)benzonitrile as a light yellow oil (17.9 g, 56%). 1H NR (400 MHz, CDCl3) δ 1.32-1.43 (m, 3H), 1.51-1.55 (m, 1H), 1.62-1.69 (m, 2H), 1.79-1.95 (m, 4H), 4.31-4.36 (m, 3H), 6.23-6.27 (m, 2H), 7.18 (d, J=8.0 Hz, 1H). MS 329 (WO.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][C:22]([OH:24])=O)[N:20]=2)=[CH:12][CH:11]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[N:20]=2)=[CH:12][CH:11]=1
Reactant: CC1CCCN1CCOc1ccc(-c2nc(CC(=O)O)co2)cc1
Reactant: C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCN1CCOc1ccc(-c2nc(CC(=O)N3CCCCC3)co2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
A solution of (2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetic acid i53 (0.29 g, 0.87 mmol, 1 eq), piperidine (0.18 ml, 1.75 mmol, 2 eq) and triethylamine (0.36 ml, 3.6 mmol, 3 eq) in dichloromethane (20 ml) is cooled to 0° C. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.42 g, 2.17 mmol, 2.5 eq) and 1-hydroxybenzotriazole (0.12 g, 0.87 mmol, 1 eq) are then added. The mixture is stirred 24 h at room temperature, and washed two times with a saturated solution of aqueous ammonium chloride. The organic layer is dried over magnesium sulfate, filtered and concentrated under vacuum. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 97/2.7/03) affords 0.15 g of 1-[(2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)acetyl]piperidine i54.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:13]O>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cccc(O)c1

Procedure:
1 g of 3-hydroxy-benzenepropanoic acid is mixed in 20 ml of methanol and 8 drops of sulphuric acid, the reaction medium is taken to reflux for 2 hours then evaporated under reduced pressure and purified by chromatography eluting with an AcOEt/Cyclohexane mixture 50/50. 1.07 g of expected product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=O)=[C:4]([F:14])[CH:3]=1.C([Mg]Br)C.[CH2:19]([O:21]CC)[CH3:20]>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:19](=[O:21])[CH3:20])=[C:4]([F:14])[CH:3]=1
Reactant: CCOCC
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)Cc1ccc(Br)cc1F
Reaction time: 6 h
Yield: 74 %

Procedure:
A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS [801303-33-3]) (24.9 g, 95.0 mmol) in THF (100 mL) at −78° C. was treated with a 3 N solution of ethyl magnesium bromide in diethyl ether (33.25 mL, 115 mmol) and allowed to warm to 0 C and stir for a 6 h period, after which time the reaction mixture was quenched with a half saturated aqueous solution of NH4Cl (200 mL) and EtOAc (100 mL). The mixture was separated and the organic component, washed with brine (2×50 mL), dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 20% EtOAc/hexanes as eluant to afford 1-(4-bromo-2-fluorophenyl)-propanone as a pale yellow solid (16.25 g, 74%). The propanone (21.15 g, 91.6 mmol) was then dissolved in ethanol (100 mL), treated with hydrazine hydrate (4.9 mL, 100.7 mmol), and heated at reflux for 4 h. The reaction mixture was then evaporated and dissolved in ethylene glycol (100 mL) and heated at 160-165° C. for 8 h after which time the cooled reaction mixture was poured onto water (500 mL) with stirring. The aqueous mixture was neutralized, with rapid stirring, using a small amount of an aqueous saturated solution of NaHCO3 to afford a pale yellow precipitate. The solids were filtered, washed with water, and air dried to afford cyclized indazole product (16.1 g, 78%).
Reaction SMILES: C(OC([N:8]1[CH2:34][CH2:33][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([C:24]5[CH:25]=[N:26][C:27]([C:30](=[O:32])[NH2:31])=[CH:28][CH:29]=5)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[CH2:12]1[C:11]2([CH2:33][CH2:34][NH:8][CH2:9][CH2:10]2)[CH2:14][N:13]1[C@H:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([NH2:31])=[O:32])=[N:26][CH:25]=3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(-c4ccc(C(N)=O)nc4)ccc31)C2
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1ccc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCNCC3)C2)cn1
Reaction time: 3 h

Procedure:
To a mixture of 2-[(R)-5-(6-carbamoyl-pyridin-3-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (9-1a, 440 mg, 0.95 mmol) in 1,4-dioxane (10 mL) was added 5 mL of 4N HCl in dioxane. This resulted in the immediate precipitation of solids. The reaction was stirred for 3 hours. The reaction was concentrated and the residue was coevaporated with diethylether (3×) until 5-[(R)-1-(2,7-diaza-spiro[3.5]non-2-yl)-indan-5-yl]-pyridine-2-carboxylic acid amide dihydrochloride (9-1b, 414 mg, 100%) was obtained as a white solid. This material was used without further purification in the next reaction. MS (ES+) 363.1 (M+H)+. 1H NMR (CD3OD) δ 2.22-2.26 (m, 5H), 2.56-2.66 (m, 1H), 3.19-3.22 (m, 4H), 3.35 (s, 1H), 3.63-3.66 (m, 1H), 4.15 (d, 1H), 4.24 (s, 2H), 4.47 (s, 1H), 5.09 (br s, 1H), 7.85 (s, 1H), 7.81 (s, 2H), 8.29-8.31 (m, 3H), 8.45 (br s, 1H), 9.07 (br s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:11][CH2:12][OH:13])[C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1.Cl[CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>O1CCCC1>[CH3:3][C:4]1[N:5]([CH2:11][CH2:12][O:13][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]([CH3:10])=[C:7]([CH3:9])[N:8]=1
Reactant: Cc1nc(C)n(CCO)c1C
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCn1c(C)nc(C)c1C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
Sodium hydride (80% dispersion in oil) (7.8 g) was suspended in dry tetrahydrofuran (100 ml). 2-(2,4,5-Trimethylimidazol-1-yl)ethanol (20 g) was added and the suspension sonicated until there was no further gas evolution. Ethyl 4-chloroacetoacetate (21.3 g) in dry tetrahydrofuran (25 ml) was added over 0.75 hours with sonication, and sonication continued for a further 4 hours. The suspension was poured into 2N hydrochloric acid (200 ml) and the tetrahydrofuran removed under vacuum. The aqueous solution was washed with dichloromethane (3×50 ml) and then neutralised with potassium carbonate. The aqueous phase was extracted with dichloromethane (5×100 ml), the combined organic extracts dried over magnesium sulphate and solvent removed under vacuum. The crude product was chromatographed over silica eluting with a mixture of methanol and ethyl acetate (1:3) to yield the title compound as a pale red oil 13.5 g (37%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]([C:28]([N:30]1[CH:34]=[CH:33][N:32]=[C:31]1I)=[O:29])([CH3:27])([CH3:26])[CH3:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C(N(CC)CC)C.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:31]4[N:30]([C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:29])[CH:34]=[CH:33][N:32]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)C(=O)n1ccnc1I
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3nccn3C(=O)C(C)(C)C)CCC(=O)CC2)cc1OC1CCCC1
Yield: 43.2 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.28g, 0.9 mmol) and 1-tert.-butylcarbonyl-2-iodoimidazole (0.29 g, 0.97 mmol) in triethylamine (5 mL) under an argon atmosphere were added tetrakis(triphenyl-phosphine)palladium(0) (0.042 g, 4%), copper(I) iodide (0.005 g, 6%), and a small crystal of triphenylphosphine, and the mixture was heated at 80°-85° C. for 1 h. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 3:7 ethyl acetate:hexanes provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(1-tert-butylcarbonylimidazol-2-ylethynyl)cyclohexan-1-one (0.18 g, 4%), as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.17 (dd, J=8.5, 2.1 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.85 (m, 1H), 3.84 (s, 3H), 3.18 (m, 2H), 2.44 (m, 4H), 2.22 (m, 2H), 1.8-2.0 (m, 6H), 1.6 (m, 11H) ppm.
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[N:8]3[C:18]1[CH:23]=[CH:22][C:21]([C:24](=[O:26])[CH3:25])=[CH:20][CH:19]=1.[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30](Cl)=[O:31].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:27][C:28]1[CH:36]=[C:35]([CH3:37])[CH:34]=[C:33]([CH3:38])[C:29]=1[C:30]([C:17]1[CH:16]=[C:15]2[C:7]([N:8]([C:18]3[CH:19]=[CH:20][C:21]([C:24](=[O:26])[CH3:25])=[CH:22][CH:23]=3)[C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=12)=[O:31]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: CC(=O)c1ccc(-n2c3ccccc3c3ccc4ccccc4c32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-n2c3ccccc3c3cc(C(=O)c4c(C)cc(C)cc4C)c4ccccc4c32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-(4-benzo[a]carbazol-11-yl-phenyl)-ethanone (649 mg, 1.93 mmol) in CH2Cl2 (10 mL) are added 2,4,6-trimethylbenzoyl chloride (369 mg, 2.02 mmol) and AlCl3 (1.50 g, 11.24 mmol) at 0° C. After stirring for 0.5 hour, the reaction mixture is stirred for 2 hours at room temperature. The reaction mixture is poured into ice-water, and the crude product is extracted with CH2Cl2. The organic layer is washed with water and brine, dried over MgSO4. After concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of n-hexane and CH2Cl2 (1:1) to obtain an off-white solid (383 mg; 41%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 2.22 (s), 2.41 (s), 2.77 (s), 6.97 (s), 7.15 (d), 7.30-7.34 (m), 7.39 (t), 7.51 (d), 7.63 (d), 7.65 (d), 8.01 (d), 8.28 (d), 8.28 (d), 8.39 (s), 9.53 (d).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:18]([C:20](=[O:22])[CH3:21])[CH3:19])[C:4]2[C:9]([C:10]=1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:23][Li]>>[OH:22][C:20]([CH3:23])([CH3:21])[CH:18]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[C:2]1[CH3:1])[CH3:19]
Reactant: [Li]C
Reactant: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2ccccc21
Product: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(C)C(C)(C)O
Temperature: -78 °C

Procedure:
A 50 mL round bottom flask was charged with (±)-tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-indole-3-carboxylate (0.2441 g, 0.810 mmol), vac/purged with N2, diluted with THF (5 mL) and cooled to −78° C. Methyllithium (0.648 ml, 0.972 mmol) was then added slowly, drop-wise, and the solution was allowed to slowly warm to ambient temperature. The reaction was then quenched with 1N HCl, extracted with EtOAc. The org layer was washed with water then brine, dried over Na2SO4, filtered, concentrated, purified by column chromatography using 10% EtOAc in Hex (10CV), 15% (10CV) to elute (±)-tert-butyl 1-(3-hydroxy-3-methylbutan-2-yl)-2-methyl-1H-indole-3-carboxylate (157.2 mg, 61.1%). LRMS (M+H+) m/z: calcd 318.42. found 318.2.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20]>CO.C(O)C>[CH3:18][S:19]([NH:22][C:14](=[NH:17])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: CS(N)(=O)=O
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)NC(=N)CCSCc1csc(NC(=N)N)n1
Yield: 56.9 %

Procedure:
In 10 ml of methanol were dissolved 1 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 0.38 g of methanesulfonamide and after causing reaction for 48 hours at room temperature, the solvent was distilled off under reduced pressure. Then, the residue formed was dissolved in 3 ml of ethanol and the solution was allowed to cool, thereby white crystals deposited. The crystals were collected by filtration and dried to provide 0.7 g of N-methanesulfonyl-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine. The product shows the following physicochemical properties: