Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:41])([CH3:40])[C:3](=[O:39])[CH:4]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([S:25]([CH3:28])(=[O:27])=[O:26])([CH3:24])[CH3:23])[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1.CC(C)([O-])C.[K+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:58])(=O)=O)=CC=1>C1COCC1.CN(C=O)C.[Cl-].[NH4+].C(OCC)(=O)C>[F:58][C:4]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1)([C:3](=[O:39])[C:2]([OH:1])([CH3:41])[CH3:40])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]([C:22]([S:25]([CH3:28])(=[O:26])=[O:27])([CH3:23])[CH3:24])[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:7]=1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(O)C(=O)C(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)C(=O)C(F)(Cc1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)c1ccc(S(C)(=O)=O)cc1
Temperature: 21 °C
Reaction time: 0.25 h

Procedure:
To a solution of Example 1 (200 mg, 0.34 mmol) in THF/DMF (1:1, 10 mL) at 0° C. was added potassium tert-butoxide (1M, THF, 0.34 mL, 0.34 mmol) dropwise. After 15 min, N-fluorobenzene sulfonimide (212 mg, 0.73 mmol) was added and the reaction mixture stirred for 2 h at 21° C. The resulting mixture was diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with toluene/acetone, 80:20) provided the title compound.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([CH3:14])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Product: Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4(-methyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [C:1]([C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][CH2:24][N:25]([CH2:28]CO)[CH2:26][CH3:27].Cl>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].CCOCC>[C:1]([C:9]1[CH:22]=[CH:21][C:12]([O:13][C:14]([CH3:20])([CH3:19])[C:15]([O:17][CH2:18][CH2:28][N:25]([CH2:26][CH3:27])[CH2:24][CH3:23])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CCO
Reactant: COC(=O)C(C)(C)Oc1ccc(C(=O)c2ccccc2)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: CCN(CC)CCOC(=O)C(C)(C)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 120 °C

Procedure:
299 g (1 mole) of methyl 2-(p-benzoylphenoxy)-2-methylpropionate, 30 g of titanium isopropylate and 117 g (1 mole) of diethylaminoethanol are placed in a 500-cc flask. The reaction mixture is heated for 45 minutes at 120° C (interior temperature) so as to distil off all the alcohol formed. The mixture is then allowed to cool and poured on to 10% hydrochloric acid in the presence of ether. The aqueous phase is made alkaline and then extracted with methylene chloride. The organic phase is carefully washed with water, then dried, decolorised and concentrated under vacuum. The residual oil is the desired ester. Yield 264 g, 69%. The maliate salt melts at 62° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].C(NC(C)C)(C)C.[Li].C(OB(OC(C)C)OC(C)C)(C)C.[Cl:39][C:40]1[N:45]=[C:44](Cl)[C:43]([CH3:47])=[CH:42][N:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([C:42]3[C:43]([CH3:47])=[CH:44][N:45]=[C:40]([Cl:39])[N:41]=3)[S:13][C:12]=2[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccsc2c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: Cc1cnc(Cl)nc1-c1cc2ccc(NC(=O)OC(C)(C)C)cc2s1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 19.8 %

Procedure:
Benzo[b]thiophen-6-yl-carbamic acid tert-butyl ester (1.06 g, 4.30 mmol) is dissolved in THF (40 mL) and cooled to −78° C. Lithium diisopropylamine solution (8.5 mL of 2.0 M solution) and triisopropylborate (6.0 mL, 26 mmol) are added. The reaction is stirred at −78° C. for 90 minutes before the cooling bath is removed. After stirring for three hours, 2,4-dichloro-5-methylpyrimidine (0.74 g, 4.5 mmol), 1,1′-bis(diphenylphosphino) ferrocene (120 mg, 0.220 mmol), palladium (II) acetate (50.4 mg, 0.220 mmol), and sodium carbonate (9.5 mL of 2.0 N solution) are added. The reaction is heated at 70° C. for 20 hours. After the reaction solution is cooled to 25° C., water (100 mL) is added. The mixture is extracted with dichloromethane and the extracts are evaporated. The resulting solid is chromatographed on silica gel, eluting with EtOAc in hexanes 5-50%, to give the title compound as a yellow solid (0.32 g, 20% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(O)C.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([N:36]=[C:37]=[S:38])=[O:35]>C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([NH:36][C:37]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[C:17]([F:23])[CH:18]=1)=[S:38])=[O:35]
Reactant: O=C(N=C=S)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (61 mg, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CS(O[CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([CH3:12])=[C:4]([CH:3]=1)[O:13][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1
Reactant: COC(=O)c1cc(Cl)cc(O)c1C
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Temperature: 75 °C
Yield: 81.5 %

Procedure:
A mixture of methyl 5-chloro-3-hydroxy-2-methylbenzoate (1.25 g, 6.23 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (3.66 g, 13.08 mmol) and cesium carbonate (5.08 g, 15.58 mmol) in DMF (25 mL) was heated at 75° C. for 18 h. The reaction was allowed to cool to ambient temperature and poured into ice/water (200 mL) with stirring. The mixture was extracted with EtOAc (3×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The light yellow residue was purified by flash chromatography (5-50% EtOAc/hexanes) to give tert-butyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (1.95 g, 5.08 mmol, 82% yield) as a solid. 1H NMR (DMSO-d6) δ 7.37 (d, J=2.0 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 4.71 (dt, J=7.4, 3.8 Hz, 1H), 3.83 (s, 3H), 3.54-3.63 (m, 2H), 3.22-3.31 (m, 2H), 2.28 (s, 3H), 1.83-1.93 (m, 2H), 1.51-1.63 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:20])[CH:13]=2)[CH:9]=[N:8][CH:7]=1.CCN(CC)CC.[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:37](=[O:45])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=1)=O.[BH3-]C#N.[Na+]>CO>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:10]2[C:6]([CH2:5][CH2:4][NH:3][CH2:28][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([OH:44])[CH:39]=3)=[CH:7][N:8]=[CH:9]2)=[CH:13][C:14]=1[F:20])#[N:17]
Reactant: N#Cc1ccc(Cn2cncc2CCN)cc1F
Reactant: O=Cc1ccccc1NC(=O)c1cccc(O)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CCNCc2ccccc2NC(=O)c2cccc(O)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-imidazol-1-ylmethyl]-2-fluoro-benzonitrile dihydrochloride (Step F) (0.64 g, 2.03 mmol) in MeOH (15 mL) was added NEt3 dropwise to pH=4.5. To this solution was added N-(2-formyl-phenyl)-3-hydroxy-benzamide (0.64 g, 2.64 mmol) and NaCNBH3 (0.255 g, 4.06 mmol), and the reaction was stirred 18 h at 25° C. The MeOH was removed in vacuo, and the residue was partitioned with EtOAc and saturated NaHCO3. The organic layer was separated and washed 3× with 10% HCl. The acidic layers were combined, made basic with Na2CO3, then extracted 3× with EtOAc. These layers were combined, washed with brine and dried (MgSO4). Filtration and concentration in vacuo gave the crude product which was purified by prep HPLC to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:13][C:14]([N:16]1[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]1[C:22]#[N:23])=[O:15]>>[OH:11][CH2:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:3][CH2:4]1)[CH2:7][CH2:6]2
Reactant: NC12CCC(CO)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(CO)(CC1)CC2
Yield: 93.3 %

Procedure:
Using 4-amino-1-hydroxymethylbicyclo[2,2,2]octane (50.0 mg) and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (75.7 mg), the same procedure was followed as in Example 5 to obtain (2S,4S)-1-[[N-(4-hydroxymethylbicyclo[2,2,2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (93.0 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].[C:17]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].[OH-].[K+]>C(O)C>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:25]=[CH:15][C:14]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH:10]=[C:11]([CH3:12])[CH3:13])=[CH:7][C:2]=2[OH:1])=[O:16])=[CH:27][CH:28]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)c1ccc(OCC=C(C)C)cc1O
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)=CCOc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)c(O)c1
Temperature: 40 °C
Reaction time: 19 h
Yield: 53 %

Procedure:
To a solution of 54.4 g of 2'-hydroxy-4'-(3-methyl-2-butenyloxy)acetophenone and 40.0 g of 4-t-butylbenzaldehyde in 1000 ml of ethanol was added 81.2 g of potassium hydroxide, and the mixture was stirred at 40° C. for 19 hours. After neutralization with dilute hydrochloric acid, the resulting precipitate was collected by filtration, washed with water, dried and recrystallized from isopropanol to give 47.6 g of 4-t-butyl-2'-hydroxy-4'-(3-methyl-2-butenyloxy)chalcone as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Mg].II.BrC1SC2C=CC=CC=2C=1.CON(C)[C:27](=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30]>O1CCCC1>[S:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([C:27](=[O:32])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH:10]=[CH:9][C:5]1=2
Reactant: CON(C)C(=O)CC(C)C
Reactant: Brc1ccc2sccc2c1
Agent: Brc1cc2ccccc2s1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A few drops of a solution of 5-bromobenzo[b]thiophene (2 g; prepared in a manner similar to that described in Example 21) in tetrahydrofuran (10 ml) was added under nitrogen to a mixture of magnesium turnings (0.24 g), tetrahydrofuran (2 ml) and a few small crystals of iodine, heat was applied to initiate the reaction, then the remainder of the bromobenzo[b]thiophene solution was added at reflux temperature over 10 minutes. When the addition was complete, the mixture was heated under reflux for 1 hour, then a solution of N-methoxy-N,3-dimethylbutyramide (1.43 g) in tetrahydrofuran (10 ml) was added. The mixture was heated under reflux for 1 hour, cooled to ambient temperature, then quenched by the addition of 2M hydrochloric acid (25 ml) and stirred at ambient temperature for 5 minutes. The majority of the tetrahydrofuran was removed in vacuo, then water (25 ml) was added to the residue and the product was extracted into ethyl acetate (2×25 ml). The extracts were washed with water (25 ml) and saturated aqueous sodium chloride solution (25 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) followed by a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-5-yl)-3-methylbutan-1-one (1.25 g) as an off-white solid which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][NH:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:11]=1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:44]([S:41]([N:38]1[CH2:37][CH2:36][CH:35]([C:26]2[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=[C:23]([C:10]4[CH:9]=[N:8][CH:7]=[C:6]([CH2:5][NH:4][CH2:3][CH:2]([CH3:1])[CH3:21])[CH:11]=4)[CH:24]=3)[NH:28][CH:27]=2)[CH2:40][CH2:39]1)(=[O:43])=[O:42])[CH3:45]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)CNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC(C)C)c4)cc23)CC1
Yield: 35 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), isobutylamine (0.013 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 21 mg of crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude (2-methylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 12.5 mg of the title compound (35%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:10]2[C:11](=[O:22])[N:12]([CH2:19][CH2:20][CH3:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[NH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>O1CCOCC1>[CH2:1]([NH:5][C:6]1[C:10]2[C:11](=[O:22])[N:12]([CH2:19][CH2:20][CH3:21])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[C:9]=2[N:8]([C:30]([O:31][CH3:32])=[O:33])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1n[nH]c2c1c(=O)n(CCC)c1ccccc21
Reactant: COC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCCNc1nn(C(=O)OC)c2c1c(=O)n(CCC)c1ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
In 60 ml of dioxane was suspended 1.40 g (4.7 mmol) of Compound 2, and 1.0 ml (7.2 mmol) of triethylamine and 0.73 ml (9.4 mmol) of methyl chlorocarbonate were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was dried under reduced pressure, and the residue was partitioned between chloroform and water. The chloroform layer was dried under reduced pressure, and the residue was passed through a silica gel column and eluted with a 3:1 (by volume) mixed solvent of hexane and ethyl acetate. The main fraction collected was recrystallized from hexane-ethyl acetate to obtain 0.67 g (40%) of the titled compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C[Al](C)C.[Br:14][C:15]1[S:19][C:18]([C:20]#[N:21])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Br:14][C:15]1[S:19][C:18]([C:20]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])=[NH:21])=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(Br)s1
Reactant: Nc1c(Cl)cccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: N=C(Nc1c(Cl)cccc1Cl)c1ccc(Br)s1
Temperature: 90 °C
Reaction time: 5 h
Yield: 103.2 %

Procedure:
To a stirred solution of 2,6-dichloroaniline (1.75 g, 10.8 mmol) in toluene (25 mL, anhyd) was added dropwise a 2.0M solution of trimethylaluminum in toluene (8.0 mL, 16 mmol). After 90 min the reaction mixture was charged with a solution of 5-bromothiophene-2-carbonitrile (3.00 g, 16 mmol) in toluene (20 mL, anhyd) and then heated at 90° C. After 5 h the reaction mixture was allowed to cool to ambient temperature and quenched by addition to a stirred slurry of silica (25 g) in 3:1 CHCl3/MeOH (100 mL). After 30 min the resulting mixture was filtered and the solids rinsed with MeOH and DCM. The combined filtrates were concentrated to afford the title compound (3.9 g, quant) as a pale yellow solid, which was used in the next step without purification. GC-MS (EI): 348, 350, 352.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:35]5[CH:44]=[C:43]6[C:38]([CH:39]=[CH:40][CH:41]=[N:42]6)=[CH:37][CH:36]=5)=[CH:3][CH:4]=4)[C:9]([OH:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: O=C(O)C(c1ccc(Br)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)C(c1ccc(-c2ccc3cccnc3c2)cc1)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Yield: 32 %

Procedure:
A solution of 2-(4-bromophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetic acid (0.402 mmol) in 1,4-dioxane (2 mL) and ethanol (0.2 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.442 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.020 mmol) and 2M aq potassium carbonate (0.602 mL). The vessel was purged with nitrogen, sealed and the reaction irradiated in a Biotage Initiator microwave at 120° C. for 10 min. The resulting black solution was then diluted with water (50 mL) and brine (10 mL), and the aqueous solution was sequentially extracted with dichloromethane and tetrahydrofuran. Only the tetrahydrofuran layer contained the product. The aqueous layer was concentrated in vacuo and the resulting solid was triturated with ethanol. The ethanol solution was filtered and added to the tetrahydrofuran layer. This organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the crude material by reverse phase HPLC (10-35% acetonitrile/water with 0.1% NH4OH) afforded the title compound as a white solid (32%). MS(ES)+ m/e 472.4 [M+H]+.
Reaction SMILES: CO.[ClH:3].Cl.Cl.[N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([NH:16][C:17]([NH:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[NH:21])=[NH:18])[CH:7]=1.[CH3:31][C:32]([CH3:34])=O>>[ClH:3].[ClH:3].[NH2:18][C:17]1[N:16]([C:8]2[CH:7]=[N:6][C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:32]([CH3:34])([CH3:31])[N:21]=[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[N:19]=1
Reactant: CCCCCCCCNC(=N)NC(=N)Nc1cnc2ccccc2c1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCNC1=NC(C)(C)N(c2cnc3ccccc3c2)C(N)=N1

Procedure:
150 ml of methanol, 120 ml of acetone and 0.5 ml of concentrated hydrochloric acid were added to 7.0 g (18.6 mmol) of N1-(3-quinolyl)-N5-octyl-biguanide dihydrochloride. The mixture was refluxed for 26 hours, and 1.8 ml of concentrated hydrochloric acid was further added thereto. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1)) to obtain 5.3 g of a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: Brc1ccc2ncccc2c1
Product: Fc1ccc2c(c1)c1c(n2-c2ccc3ncccc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 6-bromoquinoline (312 mg, 1.5 mmol; TCI-US) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.23 (m, 4H) 2.90-2.97 (m, 1H) 3.07-3.30 (m, 4H) 4.31 (s, 2H) 6.85 (td, J=9, 3 Hz, 1H) 7.06 (dd, J=9, 4 Hz, 1H) 7.12 (dd, J=10, 2 Hz, 1H) 7.64 (dd, J=8, 4 Hz, 1H) 7.73 (dd, J=9, 2 Hz, 1H) 7.97 (d, J=2 Hz, 1H) 8.23 (d, J=9 Hz, 1H) 8.47 (d, J=8 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.