Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:21][N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19]2[C:29]3[C:12]1=[N:13][NH:14][C:15]=3[N:16]=[C:17](SC)[N:18]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=O)C=1.ClCCl.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50][NH2:51]>CS(C)=O>[CH2:1]([NH:8][C:9]([CH:11]1[C:12]2[C:29]3[C:15]([NH:14][N:13]=2)=[N:16][C:17]([NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46])=[N:18][C:19]=3[N:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: CSc1nc2c3c(n[nH]c3n1)C(C(=O)NCc1ccccc1)CN2Cc1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CS(C)=O
Solvent: ClCCl
Product: CN(C)CCCNc1nc2c3c(n[nH]c3n1)C(C(=O)NCc1ccccc1)CN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N,5-dibenzyl-7-(methylthio)-1,3,4,5-tetrahydro-1,2,5,6,8-pentaazaacenaphthylene-3carboxamide (0.065 g, 0.15 mmol), 3-chloroperbenzoic acid (0.057 g, 0.33 mmol), and dichloromethane (3 mL) were placed in a screw top 2-dram vial and shaken at room temperature for 4 hours. The reactions were quenched by addition of sat NaHCO3 (2 mL). The layers were separated and the organic layers was washed with water (2×3 mL). The organic layer was concentrated under reduced pressure in Genevac centrifugal evaporation system. To the vials containing sulfone were placed N1,N1-dimethylpropane-1,3-diamine (0.45 mmol) and DMSO (1 mL). The vials were capped and shaken at 120° C. for 10 hours. The crude product was purified using reverse phase column chromatography using a Maccel AQ C18 column and a gradient of 1-95% ACN/water containing 0.05% trifluoroacetic acied, to yield the desired products in acceptable purities by LC/MS. LC-Mass: m/e 485 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O1[C:19]2([CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)[CH2:20]2)[O:18]CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CC(C)=O.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([N:21]3[CH2:22][CH2:23][C:19](=[O:18])[CH2:20]3)=[CH:25][CH:26]=2)=[O:12])=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(N2CCC3(C2)OCCO3)cc1
Reactant: CCCCOc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC(=O)C3)cc2)cc1

Procedure:
4-Butoxybenzoic acid was reacted with 4-(1,4-dioxa-7-azaspiro[4,4]non-7-yl)phenylamine by method E. The resulting amide (0.25 g) in acetone (10 ml) was mixed with para-toluenesulfonic acid (monohydrate, 109 mg), and the mixture was refluxed for 8 hours. After addition of triethylamine (0.5 ml), the mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 352.44 (C21H24N2O3); MS (ESI): 353 (M+H+) was obtained in this way.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18](O)=[O:19].Cl.C(N=C=NCCCN(C)C)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:36][CH:35]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]([F:16])([F:15])[F:17])=[CH:11][CH:12]=2)[C:3]=1[C:18]([N:43]1[CH2:42][CH2:41][N:40]([C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)[CH2:45][CH2:44]1)=[O:19]
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 75 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(4-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (621 mg, 1.38 mmol, 75%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:42]2[CH:43]=[CH:44][C:39]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:40][CH:41]=2)=[CH:25][CH:24]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Br)cc1)N(C(=O)OC(C)(C)C)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)C(Cc1ccc(-c3ccc(-c4ccccc4)cc3)cc1)N(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6,7-Dimethoxy-1-[1,1′;4′,1″]terphenyl-4-ylmethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (12) was prepared as follows: A mixture of 0.462 g (1 mmol) of 1-(4-Bromo-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester and 0.297 g (1.5 mol. equiv.) of 4-biphenylboronic acid in 4 ml of isopropanol was stirred under argon at room temperature for 30 min. To this mixture, 1 mg (0.45 mol %) of Palladium(II)acetate, 4 mg (1.3 mol %) of triphenylphosphine, and 0.6 ml (1.2 mol. equiv.) of 2M sodium bicarbonate aqueous solution were added successively and the mixture was refluxed with stirring for 6 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between 50 ml of ethyl acetate and 25 ml of 5% sodium hydroxide aqueous solution. After shaking, the organic layer was washed with water (25 ml) and brine (25 ml), and then dried with sodium sulfate. The solvent was evaporated under reduced pressure and the remaining oil was crystallized by trituration with n-hexanes. The solid was recrystallized using ethyl acetate\n-hexanes mixture to give 0.40 g (75%) of white solid, mp 153-155° C.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][CH:34]=1)[C:23]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[O:24].C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:22]2[CH:21]=[C:20]([NH:19][C:3]([C:5]3[CH:6]=[CH:7][N:8]4[C:12]=3[CH2:11][S:10][CH:9]4[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:4])[CH:34]=[CH:33][CH:32]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(c1ccc(Cl)cc1)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 66 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 66° and 72° C., to a solution of 3-amino-4'-chlorobenzophenone (4.6 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 66° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 8 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 Kpa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 2N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (9.8 g) is thereby obtained, which is dissolved in boiling acetonitrile (250 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 10° C. for 3 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (45 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(4-chlorobenzoyl)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.2 g) in the form of pale yellow crystals, m.p. 176° C., is thereby obtained.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:16]=[C:15]([C:17]#[N:18])[C:14]([NH:19]CC3C=CC(OC)=CC=3)=[N:13][C:12]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:5]1)([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.CCCCCC.CCOC(C)=O>O.C(Cl)(Cl)Cl>[NH2:19][C:14]1[C:15]([C:17]#[N:18])=[N:16][C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=2)=[C:12]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:13]=1
Reactant: COc1ccc(CNc2nc(-c3ccccc3)c(-c3ccc(=O)n(C(C)C)n3)nc2C#N)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)n1nc(-c2nc(C#N)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 27.5 °C
Reaction time: 10 h
Yield: 77.3 %

Procedure:
To a solution of 6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-3-[(4-methoxybenzyl)amino]-5-phenyl-2-pyrazinecarbonitrile (590 mg) in a mixture of water (1.5 ml) and CHCl3 (30 ml) was added 4,5-dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (888 mg). The reaction mixture was stirred at 25-30° C. for 10 hours, washed with 1N aq. NaOH solution, dried over MgSO4 and concentrated under reduced pressure to give a residue. The residue was subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile as a solid (335 mg).
Reaction SMILES: [NH2:1]CCC[Si](OC)(OC)OC.[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].[C:17]([OH:21])(=[O:20])C=C.C(O)(=O)[CH:23]=[CH2:24].C(C(CO)(CO)CC)O.C(O)(C)C>C(O)(=O)C>[C:12]([OH:16])(=[O:15])[CH:13]=[CH2:14].[NH2:1][C:17]([O:21][CH2:23][CH3:24])=[O:20]
Reactant: CO[Si](CCCN)(OC)OC
Agent: C=CC(=O)O
Agent: CCC(CO)(CO)CO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CCOC(N)=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5.40 g of 3-aminopropyltrimethoxysilane, 6.80 g of hexanedioldiacrylate, 19.0 g of trimethylolpropane triacrylate, and 57.9 g of isopropanol is stirred at room temperature for 72 hours. To the mixture, 1.15 g of acetic acid is added, and the mixture is stirred for 5 minutes. Next, 56.2 g of NALCO 1034A is added under vigorous agitation. The resulting mixture is stirred at room temperature for 1 hour. 0.34 g of a solution of EBECRYL 1360 (50% by weight in PM glycol ether) and 1.80 g of DAROCUR 1173 are added. The resulting coating composition is stirred for an additional 30 minutes to ensure mixing.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[CH:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1)=O.[F:33][C:34]([F:51])([F:50])[CH2:35]P(=O)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[F:33][C:34]([F:51])([F:50])/[CH:35]=[CH:19]/[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([O:31][CH3:32])[CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1OC
Reactant: O=P(CC(F)(F)F)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/C(F)(F)F)cc1OC
Reaction time: 8 h

Procedure:
MS 4 Å (powder, 16 g) was added to a 1 M solution of TBAF in THF (20 mL, 20 mmol), and the mixture was stirred at room-temperature overnight under an argon atmosphere. To the mixture were added a solution of methyl 4-formyl-2-methoxybenzoate (420 mg, 0.0022 mol) and 2,2,2-trifluoroethyldiphenylphosphine oxide (1.23 g, 0.00432 mol) in THF (20 mL). After the mixture was stirred for 2 h, MS 4 Å was removed by filtration. The filtrate was concentrated and water (120 mL) was added. The mixture was extracted with AcOEt. The extract was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography on silica gel using AcOEt-hexane (0-15%) as eluent to give (E)-methyl 4-(3,3,3-trifluoroprop-1-enyl)-2-methoxybenzoate as a white solid, followed by (Z)-methyl 4-(3,3,3-trifluoroprop-1-enyl)-2-methoxybenzoate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[O:7])=[C:4]([F:19])[CH:3]=1.N[CH:21]1CCN(C)CC1>>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH3:21])[CH2:11][CH2:10]2)=[O:7])=[C:4]([F:19])[CH:3]=1
Reactant: CN1CCC(N)CC1
Reactant: CN1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1
Product: CCN1CCC(NC(=O)c2cc(Cl)c(N)cc2F)CC1

Procedure:
The title compound was prepared by an analogous method to the preparation of Intermediate 173, on a 2.64 mol scale, utilising 4-amino-1-methylpiperidine (Fluorochem; 508 mg, 3.96 mmol) after purification on a silica column (gradient (3-4% ammonia in methanol/DCM), as a pale brown foam (647 mg, 82%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]1([N:25]2[CH2:32][CH2:31][CH2:30][C@H:26]2[C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:27]([C:26]2[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:32]=[CH:31][CH:30]=2)=[O:28])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C(O)[C@@H]1CCCN1c1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cccn2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.30 g, 1.03 mmol), 1-phenylproline obtained in Reference example 7 (0.21 g, 1.08 mmol), triethylamine (0.22 g, 2.16 mmol), EDCI (0.21 g, 1.08 mmol) and HOBt (0.17 g, 1.08 mmol) in acetonitrile (10 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water, and the suspension of white precipitate in ethyl acetate was washed with 10% sodium hydrogen carbonate solution, water, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 30:70) to afford the title compound (0.10 g, 25%) as a light brown amorphous powder.
Reaction SMILES: CC[O-].[Na+].[CH2:5]([SH:9])[CH2:6][CH2:7][CH3:8].Cl[CH:11]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13][CH2:12]1>C(O)C>[CH2:5]([S:9][CH:11]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[CH2:13][CH2:12]1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCS
Reactant: O=C1CCC(Cl)CCN1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCSC1CCNC(=O)CC1

Procedure:
6.8 g (0.1 mol) of sodium ethylate and 9 g (0.1 mol) of butanethiol are initially introduced into 100 ml of ethanol, and 14.8 g (0.1 mol) of 5-chloro-azacycloheptan-2-one are added at room temperature. After the mixture has been boiled under reflux for 10 hours, the precipitated sodium chloride is filtered off under suction, the mother liquor is evaporated down in vacuo and the residue is distilled.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([C:28]2[CH:29]=[C:30]4[C:50](=[CH:51][CH:52]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:37][C:33]=2[CH2:32][CH2:31]4)[CH:22]=[CH:21]3)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([C:28]2[CH:29]=[C:30]4[C:50](=[CH:51][CH:52]=2)[C:34]2[NH:35][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:37][C:33]=2[CH:32]=[CH:31]4)[CH:22]=[CH:21]3)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(c4)CCc4nc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]c4-5)ccc3c2)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119 %

Procedure:
Manganese(IV) oxide (1.53 g, 17.6 mmol) was added to a solution of (S)-tert-butyl 2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (183 mg, 0.196 mmol) in DCM (5 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through a pad of diatomaceous earth (CELITE®) and washed with a solution of methanol/DCM 1:1. The volatiles were removed under vacuum using a rotavap to afford (S)-tert-butyl 2-(7-(6-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (163 mg) as tan solid. LC-MS retention time 1.523 min; m/z 699.53 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=1[C:13]([CH2:15][C:16](OCC)=[O:17])=O>>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:13]([C:12]1[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=1[O:10][CH3:9])[CH:15]=[C:16]2[OH:17]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(=O)CC(=O)c1ccccc1OC
Product: COc1ccccc1-c1cc(O)c2cc(Cl)ccc2n1

Procedure:
Prepared according to procedure R using 4-chloroaniline (774.0 mg, 6.1 mmol), ethyl (2-methoxybenzoyl)acetate (2.0 mL, 10.3 mmol), and PPA (4.70 g, 47.0 mmol) to afford 6-chloro-2-(2-methoxyphenyl)quinolin-4-ol. Mass Spectrum (ESI) m/e=286.0 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[C:9]([NH:10][C:11]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[N:14]=[C:13]([C:21]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:22]=3[F:28])[N:12]=2)=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[Br:27][C:25]1[CH:24]=[CH:23][C:22]([F:28])=[C:21]([C:13]2[N:12]=[C:11]([NH:10][C:9]3[C:4]([C:3]([OH:29])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=3)[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[N:14]=2)[CH:26]=1
Reactant: COC(=O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnccc1Nc1nc(-c2cc(Br)ccc2F)nc2nccnc12
Yield: 82.6 %

Procedure:
A solution of 4-[[2-(5-bromo-2-fluorophenyl)pteridin-4-yl]amino]nicotinic acid methyl ester 107 (200 mg, 0.439 mmol) and NaOH (44 mg, 1.10 mmol) in THF/MeOH/H2O (3:2:1, 5 mL), was stirred at room temperature for 3 h. The solvent was evaporated, and the residue dissolved in H2O, neutralized with AcOH, filtered off, and successively washed with H2O, MeOH and Ether to give 160 mg of the title product 16 as a yellow powder (LCMS analysis).
Reaction SMILES: [CH3:1][C:2]([NH:34]C(=O)OC(C)(C)C)([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]3[C:15]4[CH:27]=[CH:26][CH:25]=[N:24][C:16]=4[NH:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:13]3=[N:12][C:11]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)[CH3:3].[ClH:42]>ClCCl.O1CCOCC1>[ClH:42].[C:28]1([C:11]2[N:12]=[C:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]4[N:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]3[C:10]=2[C:7]2[CH:6]=[CH:5][C:4]([C:2]([NH2:34])([CH3:1])[CH3:3])=[CH:9][CH:8]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(N)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Reaction time: 5 h
Yield: 85 %

Procedure:
To a solution of tert-butyl {1-methyl-1-[4-(2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]ethyl}carbamate (41 mg) in dichloromethane (4 mL) was added hydrogen chloride in 1,4-dioxane (2.5 mL) dropwise at room temperature. After being stirred at the same temperature for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was suspended with ethyl acetate and filtered to give the product (37 mg, 85%). 1HNMR (DMSO-d6) 400 MHz δ: 8.72-8.62 (m, 3H), 8.11 (dd, J=4.6, 1.8 Hz, 1H), 7.96 (dd, J=7.8, 1.4 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.52-7.47 (m, 2H), 7.42-7.25 (m, 7H), 7.17-7.11 (m, 1H), 6.88 (dd, J=8.0, 1.8 Hz, 1H), 6.74 (dd, J=8.0, 4.6 Hz, 1H), 1.63 (s, 6H). LCMS: 444 [M+H].
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH3:11])[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)(=O)/C=C/C(O)=O>>[CH2:10]([O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[N:3]=[C:2]1[N:20]1[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]1)[CH3:11]
Reactant: CN1CCNCC1
Reactant: CCOCCn1c(Cl)nc2ccccc21
Agent: O=C(O)/C=C/C(=O)O
Product: CCOCCn1c(N2CCN(C)CC2)nc2ccccc21

Procedure:
In the same manner as described in Example 1 using 2-chloro-1-[2-(ethoxy)ethyl]benzimidazole (100.0 g), N-methylpiperazine (90.0 g) and fumaric acid (83.0 g), there are obtained crude crystals, which are recrystallized from ethanol to give 1-[2-(ethoxy)ethyl]-2-(4-methyl-1-piperazinyl)benzimidazole.3/2 fumarate (148.0 g) as colorless plates, m.p. 167.5°-168.5° C.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[S:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:13]2[C:7]3[C:6]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=4[S:19][C:8]=3[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:37][CH2:36]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2Sc2sc3c(c21)CCCC3
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3Sc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11 H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[CH3:10][C:11]1[C:12]([S:17](Cl)(=[O:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:17]([C:12]2[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:19])=[O:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1cccnc1S(=O)(=O)Cl
Product: COc1ccc(NS(=O)(=O)c2ncccc2C)cn1

Procedure:
prepared by reaction of 6-methoxy-pyridin-3-ylamine with 3-methyl-pyridine-2-sulfonyl chloride