Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Cl.O.C(Cl)(Cl)Cl.[CH3:15][CH2:16][C@@H:17]([C:19](O)=[O:20])[CH3:18]>[Cl-].[Zn+2].[Cl-]>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:19](=[O:20])[CH:17]([CH3:18])[CH2:16][CH3:15]
Reactant: CC[C@H](C)C(=O)O
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC(C)C(=O)c1ccc(O)cc1O
Temperature: 110 °C
Yield: 31.7 %

Procedure:
16.3 g of anhydrous zinc chloride was dissolved in 10.3 g of S-(+)-2-methylbutanoic acid by heating to 110° C. 13.2 g of resorcinol was added to the mixture and then the temperature of the admixture was raised to 150° C. over a period of 30 minutes under stirring. The reaction mixture was then cooled to the room temperature, and a mixture composed of 25 ml of hydrochloric acid and 25 ml of water was added thereto. The reaction mixture was then subjected to extraction for three times, each by using 50 ml of ethyl ether. The extracts were joined together and rinsed with an aquesous solution of NaHCO3 for three times, and then rinsed with water for three times. Anhydrous Na2SO4 was added to the rinsed extract to dry the ethyl ether extract. Ethyl ether was removed to obtain a liquid reaction product which was refined through silica gel column chromatography while using chloroform as the eluent. As a result, 6.2 g of 3-hydroxy-4 -(1-oxo-2-methylbutyl)phenol was obtained.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C@H:12]1[CH2:17][CH2:16][C@H](O)[CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:1]([O:9][C@H:10]1[CH2:16][CH2:17][C@H:12]([NH2:11])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: Cc1ccccc1
Product: N[C@H]1CC[C@H](OC(=O)c2ccccc2)CC1

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (1.0 mmol), trans-4-aminocyclohexan-1-ol (1.2 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and toluene (1.7 ml) was heated to reflux for 24 hours, and as a result, trans-4-aminocyclohexyl benzoate was obtained at a yield of 99%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CBr
Reactant: Cc1cccc(C)c1O
Product: CCOC(=O)COc1c(C)cccc1C

Procedure:
The title compound is prepared using essentially the same procedure used in example 42 except using 2,6-dimethylphenol in place of 4-chloro-2,6-dimethylphenol and ethyl bromoacetate in place of bromoacetonitrile.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]([N:8]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[O:7].O1CCCC1.Cl.Cl.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:51]=[CH:52][CH:53]=1)[CH2:35][N:36]1[C:40]2=[N:41][CH:42]=[N:43][C:44]([N:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)=[C:39]2[CH:38]=[N:37]1)[CH3:30].C([BH3-])#N>C(O)(=O)C.C(N(CC)CC)C>[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:51]=[CH:52][CH:53]=1)[CH2:35][N:36]1[C:40]2=[N:41][CH:42]=[N:43][C:44]([N:45]3[CH2:46][CH2:47][N:48]([CH2:18][C:17]4[CH:20]=[CH:21][C:14]([N:8]([C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=4)[CH2:49][CH2:50]3)=[C:39]2[CH:38]=[N:37]1)[CH3:30]
Reactant: CCOc1cccc(Cn2ncc3c(N4CCNCC4)ncnc32)c1
Reactant: COCCOC(=O)N(CCN(C)C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOc1cccc(Cn2ncc3c(N4CCN(Cc5ccc(N(CCN(C)C)C(=O)OCCOC)cc5)CC4)ncnc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106 %

Procedure:
To 4-[N-[(2-methoxyethoxy)carbonyl]-N-[2-(dimethylamino)ethyl]amino]-benzaldehyde (90 mg, compound obtained in Reference Example 97) is added successively tetrahydrofuran (1.5 mL), 1-(3-ethoxybenzyl)-4-(1-piperazinyl)-1H-pyrazolo[3,4-d]pyrimidine dihydrochloride (100 mg), triethylamine (90 μL), acetic acid (73 μL) and macroporous triethylammoniummethylpolystylenecyanoborohydride (MP-Cyanoborohydride 2.04 mmol/g, Argonaut Technology). The mixture is shaken at room temperature for 18 hours by using a parallel synthesizer (MiniBlock; Mettler Toledo). The reaction mixture is separated and the residual resin is washed with tetrahydrofuran (×3). The washings and the reaction solution are combined and concentrated. The resultant crude product is purified by flash column chromatography on silica gel (Solvent; ethyl acetate:chloroform=1:0→0:1) to give 1-(3-ethoxybenzyl)-4-[4-[4-[N-[(2-methoxyethoxy)carbonyl]-N-[2-(dimethylamino)ethyl]-amino]benzyl]piperazin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine (159 mg, yield; 38%) as an amorphous powder. MS (APCI) m/z: 617 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)N=N[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:27]1(C)C=CC(C)=C[CH:28]=1.C12CC(C=C1)C=C2>O>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:27]=[CH:28][C:10]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(C)cc1
Reactant: Brc1ccc(-c2nnc(-c3ncccn3)nc2-c2ccc(Br)cc2)cc1
Agent: C1=CC2C=CC1C2
Solvent: O
Product: Brc1ccc(-c2ccc(-c3ncccn3)nc2-c2ccc(Br)cc2)cc1

Procedure:
In a 200 mL three-neck flask were put 2.4 g (5.0 mmol) of 5,6-bis(4-bromophenyl)-3-(pyrimidin-2-yl)-1,2,4-triazine, 60 mL of para-xylene, 2.1 mL (19 mmol) of 2,5-Norbornadiene, and the mixture was refluxed under a nitrogen gas stream at 150° C. for 12 hours. After a certain time, water was added to the mixture, and an aqueous layer was extracted with toluene. The extract was washed with a saturated saline together with the organic layer, and the organic layer was then dried over magnesium sulfate. The mixture was subjected to gravity filtration, and the obtained filtrate was concentrated to give a solid. The obtained solid was recrystallized with chloroform/hexane, so that 1.6 g of a target substance, light-yellow solid was obtained in a yield of 67%.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Cl.Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[CH:17]=[CH:16][N:15]=1>>[N:25]1([CH2:24][CH2:23][CH2:22][S:21][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:13][S:1][C:2]3[NH:6][C:5]4[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=4[N:3]=3)[C:19]=2[CH3:20])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Cc1c(SCCCn2ccnc2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Product: Cc1c(SCCCn2ccnc2)ccnc1CSc1nc2ccccc2[nH]1

Procedure:
Following the procedure described in Example 1, the reaction of 2-mercapto-1H-benzimidazole with 2-chloromethyl-4-[3-(imidazol-1-yl)propylthio]-3-methylpyridine hydrochloride gives the title compound as a colorless solid after crystallization from diisopropyl ether; m.p. 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])O[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:29]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Solvent: CO
Product: COc1ccc(Cn2c(C(=O)O)c(-c3ccccc3)c3cc(Cl)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.9 %

Procedure:
A mixture of 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (300 mg), 4-methoxybenzylamine (684 mg) and methanol (3.0 ml) was stirred at room temperature for 12 hrs. The reaction mixture was concentrated, and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Then, 4N hydrochloric acid ethyl acetate solution (3.0 ml) was added to the residue and the mixture was stirred for 12 hrs. at room temperature. The reaction mixture was concentrated under reduced pressure and dried to give the title compound (360 mg) as a pale-yellow powder.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)(=O)[CH3:15]>>[CH3:2][C:3]1[CH:8]=[C:7]2[C:6](=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[NH:9][C:14]([C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1)=[CH:15]2
Reactant: CC(=O)c1cnccn1
Reactant: Cc1ccc(NN)c([N+](=O)[O-])c1
Agent: Cl
Product: Cc1cc([N+](=O)[O-])c2[nH]c(-c3cnccn3)cc2c1
Yield: 12 %

Procedure:
(4-Methyl-2-nitrophenyl)hydrazine hydrochloride (2 g, 9.8 mmol) and 2-acetylpyrazine (1.2 ml, 9.8 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (0.3 g, Yield 19%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH:11]=[C:10]2[C:18]([O:20]CC)=O)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:34]=[CH:33][C:27]2[N:28]([CH3:32])[C:29]([CH3:31])=[N:30][C:26]=2[CH:25]=1>>[CH3:32][N:28]1[C:27]2[CH:33]=[CH:34][C:24]([NH:23][C:18]([C:10]3[N:9]([CH2:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)[C:13]4=[N:14][CH:15]=[CH:16][CH:17]=[C:12]4[CH:11]=3)=[O:20])=[CH:25][C:26]=2[N:30]=[C:29]1[CH3:31]
Reactant: Cc1nc2cc(N)ccc2n1C
Reactant: CCOC(=O)c1cc2cccnc2n1Cc1cccc(F)c1
Product: Cc1nc2cc(NC(=O)c3cc4cccnc4n3Cc3cccc(F)c3)ccc2n1C
Yield: 86.1 %

Procedure:
The process is performed according to the method described in Example 11, starting with 0.4 g (1.34 mmol) of ethyl 1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Example 5.3) and 0.25 g (1.61 mmol) of 5-amino-1,2-dimethylbenzimidazole. 0.477 g of expected compound is isolated.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25](F)[CH:24]=2)[N:3]=1.O.[NH2:33][NH2:34]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[C:25]3[C:26]([C:29]([NH2:30])=[N:33][NH:34]3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: C[C@@H]1CO[C@H](CNC(=O)C(C)(C)C)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Reaction time: 17 h
Yield: 63.7 %

Procedure:
A mixture of crude N-({(2R,5R)-4-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methyl)-2,2-dimethylpropanamide (0.29 mmol theoretical) and hydrazine monohydrate (0.28 mL, 5.78 mmol) in ethanol (3 mL) was stirred at 100° C. in a sealed tube for 17 hours. The mixture was concentrated in vacuo and the residue was purified on a Gilson reverse phase HPLC (CH3CN/water with 0.1% TFA). The product fractions were combined and concentrated in vacuo, taken up in EtOAc (15 mL), washed with saturated aqueous NaHCO3 (2×10 mL) and brine (10 mL), then dried (Na2SO4), filtered, and concentrated in vacuo to afford the title compound (81 mg) as a pale yellow solid. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.13 (s, 9H), 1.17 (d, J=6.6 Hz, 3H), 2.64-2.84 (m, 1H), 3.20-3.30 (m, 2H), 3.42-3.52 (m, 1H), 3.63 (dd, J=11.4, 2.5 Hz, 1H), 3.77 (d, J=11.1 Hz, 1H), 3.98-4.79 (bs, 2H), 5.39 (s, 2H), 6.12 (s, 2H), 6.50 (s, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.63 (t, J=5.7 Hz, 1H), 7.71 (d, J=8.3 Hz, 1H), 7.93 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:20]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.O>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([Cl:20])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(Cl)c21
Temperature: 20 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A solution of (S)-N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.62 g, 2.1 mmol) in dichloromethane (10 mL) was treated with N-chlorosuccinimide (0.284 g, 2.1 mmol) and trifluoromethanesulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16 h at 20° C., diluted with water (20 mL) and extracted with dichloromethane (25 mL). The organics were dried with MgSO4, filtered and concentrated. HPLC purification was done to provide 0.078 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.32-7.25 (m, 1H), 6.97-6.93 (m, 1H), 4.27-4.24 (m, 0.6H), 4.19-4.13 (m, 1H), 4.08-4.01 (m, 1H), 3.91-3.86 (0.8H, m), 3.74-3.69 (m, 0.8H:), 3.45-3.37 (m, 1H), 3.31-3.21 (m, 1H), 2.96-2.80 (m, 1H), 1.28-1.22 (m, 3H). MS calculated for C13H12Cl2F3NO+H: 326, observed: 326.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH2:18][OH:19])=[C:16]([F:20])[C:15]([F:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][C:24]=1[N+:30]([O-])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH2:18][O:19][C:26]2[CH:27]=[CH:28][C:23]([Cl:22])=[C:24]([CH:25]=2)[NH2:30])=[C:16]([F:20])[C:15]([F:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(F)c(F)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(F)c(F)c1COc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
To a solution of 6-[2-(tert-butoxycarbonylamino)ethoxy]-2,3-difluorobenzyl alcohol (0.54 g), 4-chloro-3-nitrophenol (0.31 g) and triphenylphosphine (0.54 g) in tetrahydrofuran (4 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 1.03 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). To the solution were added methanol (6 mL) and nickel(II) bromide (20 mg). To the mixture was added sodium borohydride (0.2 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine twice, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−1/1) and column chromatography on amino-propylated silica gel (eluent: n-hexane/ethyl acetate=3/1−2/3) successively to give the title compound (0.75 g).
Reaction SMILES: [CH:1]1[C:18]2[C:19]3[C:24]4[C:3](=[CH:4][CH:5]=[C:6]5[C:23]=4[C:22]4[C:9](=[CH:10][CH:11]=[C:12]6[C:21]=4[C:20]=3[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13]6)[CH:8]=[CH:7]5)[CH:2]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[O:31]=[C:25]([C:2]1[C:3]2[C:24]3[C:19]4[C:18](=[CH:17][CH:16]=[C:15]5[C:20]=4[C:21]4[C:12](=[CH:11][CH:10]=[C:9]6[C:22]=4[C:23]=3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8]6)[CH:13]=[CH:14]5)[CH:1]=1)[CH2:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: O=C1CCC(=O)O1
Reactant: c1cc2ccc3ccc4ccc5ccc6ccc1c1c2c3c4c5c61
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)CCC(=O)c1cc2ccc3ccc4ccc5ccc6ccc1c1c6c5c4c3c21
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.4 %

Procedure:
The coronene 81 (0.699 g, 2.33 mmol) and 0.514 g (5.14 mmol) of succinic anhydride were put into a 100-ml two-inlet flask, and a nitrogen substitution was performed. The substance obtained here was immersed in an ice bath. After 2.80 g (21.0 mmol) of aluminum chloride dispersed in 20 ml of nitrobenzene was slowly dripped onto the substance, the reaction container was removed from the ice bath, and the substance was stirred at room temperature for 5 hours. After the reaction was completed, 10 ml of cooled 2M hydrochloric acid was added, followed by 10-minute stirring. The substance was cooled slowly down to room temperature, to precipitate a solid substance. The solid substance was collected by filtration. This solid substance was dispersed in 20 ml of xylene, and was heated to 140° C. In this manner, the solid substance was dissolved. The substance was then cooled slowly back to room temperature, to precipitate a solid substance. The solid substance obtained here was collected by filtration, and was dried under reduced pressure, to obtain 0.825 g of the yellow-green solid substance 82.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:46])=CC=1>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][C:27]4[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)=[S:46])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1ccc(NC2CCN(C(=O)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1
Product: N#Cc1ccc(NC2CCN(C(=S)CCCN3CCN(c4ccc(C(F)(F)F)cc4)CC3)CC2)cc1
Temperature: 102.5 °C

Procedure:
4-(1-{4-[4-(4-Trifluoromethyl-phenyl)-piperazin-1-yl]-butyryl}-piperidin-4-ylamino)-benzonitrile (7 mg; 0.014 mmol, prepared in accordance with Example 83) is reacted with Lawesson's reagent (3 mg; 0.007 mmol) and the resulting mixture is heated between at 95 to 110° C. for 2 hours. In cases where incomplete conversion of the starting amide is observed, additional portion of Lawesson's reagent is added and the mixture heated further until no evolution of the conversion is observed. The reaction mixture is concentrated under reduced pressure and the crude residue is purified by preparative HPLC (1 mg; 0.002 mmol). The structure was confirmed using Protocol I-B. Calculated mass=516; observed mass=516; HPLC retention time=4.53 min.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]>>[CH:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])([CH3:14])[CH3:13]
Reactant: COP(OC)OC
Reactant: CC(C)OC(=O)Cl
Product: COP(=O)(OC)C(=O)OC(C)C

Procedure:
From 10.0 ml (85 mmole) of trimethylphosphite and 7.8 g (64 mmole) of i-propyl chloroformate. (100° C., 2 hours).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]3[N:19]([CH:20]=2)[N:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=[CH:15]3)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:24]([Cu])#[N:25]>CN1CCOCC1.CO>[CH2:22]([O:21][C:17]1[CH:16]=[CH:15][C:14]2=[N:13][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([CH:3]=3)[C:24]#[N:25])=[CH:20][N:19]2[N:18]=1)[CH3:23]
Reactant: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(Br)c3)cn2n1
Reactant: N#C[Cu]
Solvent: CO
Solvent: CN1CCOCC1
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(C#N)c3)cn2n1
Temperature: 220 °C
Yield: 70 %

Procedure:
A mixture of 2-[3-bromo-4-(trifluoromethyl)phenyl]-6-ethoxy-imidazo[2,1-f]pyridazine (0.050 g, 0.129 mmol) and CuCN (0.058 g) in 4-methylmorpholine (2.0 mL) is heated in the microwave at 220° C. for 10 min. The mixture is diluted with MeOH (10 mL) and the solids are removed by filtration. The crude solution is concentrated to remove the MeOH. Water (50 mL) is added and the solid precipitate is collected. The crude product is purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.03 g, 71% yield). LCMS m/z=333.3 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]2[S:15][CH:14]=[CH:13][C:12]=2[CH:16]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH2:18]1.O.C(OCC)(=O)C>CN(C)C=O>[S:15]1[C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:17]3[CH2:20][CH:19]([NH:21][C:22](=[O:24])[CH3:23])[CH2:18]3)=[CH:16][C:12]=2[CH:13]=[CH:14]1
Reactant: ClCCCOCCc1ccc2sccc2c1
Reactant: CC(=O)NC1CNC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC1CN(CCCOCCc2ccc3sccc3c2)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 37.4 %

Procedure:
In 8 mL of N,N-dimethylformamide was dissolved 0.80 g of 5-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and 1.20 g of N-(3-azetidinyl)acetamide was added to the solution, after which the resulting mixture was stirred at 90° C. for 12 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=7:1) to obtain 0.39 g of N-(1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-azetidinyl)acetamide as a light-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.6 %

Procedure:
3,4-dichlorobenzenethiol (500 mg, 2.79 mmol) and 2-(3-bromopropyl)isoindoline-1,3-dione (823 mg, 3.07 mmol) were stirred in DMF (2 mL) at rt. Cs2CO3 (1.64 g, 5.03 mmol) was added. The reaction mixture was stirred at rt for 14 h. H2O was added and the aqueous phase was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give crude product, which was triturated with ether, filtered and dried to give Intermediate 10A (760 mg, 2.08 mmol, 74.0% yield). HPLC/MS (Method N) RT=4.00 min [M+1]+ 365.8.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH2:24]([NH:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([N:28]([CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:18][CH3:19])[N:9]=[CH:8][N:7]=[C:6]2[NH:5][C:4]1[CH:20]=[CH:21][CH:22]=[C:2]([Cl:1])[C:3]=1[F:23])[CH2:29][C:30]([OH:32])=[O:31])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNCC(=O)O
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Product: CCCCN(CC(=O)O)Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with N-butylglycine using an analogous method to that described for the equivalent step in Example 1 to give N-butyl-N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)glycine; 1H NMR Spectrum: (DMSO-d6) 0.83 (t, 3H); 1.27 (m, 2H); 1.46 (m, 2H); 2.70 (t, 2H); 3.33 (s, 2H); 3.95 (s, 5H); 7.20 (s, 1H); 7.28 (t, 1H); 7.47 (m, 1H); 7.55 (m, 1H); 8.36 (s, 1H); 8.43 (s, 1H); 9.82 (s, 1H); Mass Spectrum: (M+H)+ 447.