Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cnc(Cl)c(F)c2)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 53 using 5-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. HPLC (Condition 4) tR=5.74 min, UPLC-MS (Condition 3) tR=1.16 min, m/z=497.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.30 (s, 3H) 3.60 (s, 4H) 5.48 (s, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.00-8.15 (m, 2H) 8.38 (d, J=1.95 Hz, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH2:19]>C(#N)C.C(OC(C)C)(C)C>[Br:16][C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:18]=1[NH:19][C:14]([NH:13][C:4]1[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:15]
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: Nc1c(F)cccc1Br
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1c(F)cccc1Br
Temperature: 81 °C
Reaction time: 45 h
Yield: 87.4 %

Procedure:
2-Methoxy-5-trifluoromethylphenyl isocyanate (1.19 kg) is fused at about 35° C. and dissolved in acetonitrile (4.2 l), then 2-bromo-6-fluoroaniline (870 g) is added and rinsed out with acetonitrile (380 ml). The resulting clear solution is stirred at 74-88° C. for 45 h, then concentrated in vacuo (200 mbar) at 50° C. to give a viscous magma (amount of distillate 4.4 l). This is diluted at room temperature with diisopropyl ether (1.5 l), filtered off with suction, washed with diisopropyl ether (1.15 l) and dried at 45° C. in the VDO using entraining nitrogen to constant mass (24 h). A total of 1.63 kg of N-(2-bromo-6-fluorophenyl)-N′-[2-methoxy-5-(trifluoromethyl)phenyl]urea is obtained as a solid, corresponding to 87.5% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:26][C:27]([F:32])([F:31])[CH:28]([F:30])[F:29])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(Cl)cc1)CC(F)(F)C(F)F
Yield: 7.5 %

Procedure:
Using 1.0 g of (4-chlorobenzyl)malononitrile, 15 ml of N,N-di-methylformamide, 0.073 g of cesium carbonate, and 1.47 g of 2,2,3,3-tetra-fluoropropyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(4-chlorobenzyl)-2-(2,2,3,3-tetrafluoropropyl)malononitrile (the present compound (25)).
Reaction SMILES: N1C=CC=CC=1.[C:7]1([OH:15])[C:8](=[CH:10][C:11](=[CH:13][CH:14]=1)[OH:12])[CH3:9].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[CH3:16][S:17]([CH:9]([S:17]([CH3:16])(=[O:19])=[O:18])[C:8]1[C:7]([OH:15])=[CH:14][CH:13]=[C:11]([OH:12])[CH:10]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(O)ccc1O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)C(c1cc(O)ccc1O)S(C)(=O)=O

Procedure:
In 500 ml. of pyridine was dissolved 124 g. of toluhydroquinone and then 170 ml. of methanesulfonyl chloride was added dropwise to the solution while stirring at a temperature below 25° C. Thereafter, the mixture was further stirred for one hour at room temperature. After the reaction was over, 500 ml. of chloroform was added to the reaction mixture and the resultant mixture was washed several times with water, then with 10% hydrochloric acid and finally once with water. The chloroform layer formed was recovered and dried over anhydrous sodium sulfate. After filtering, the solvent was distilled off from the filtrate and the residue formed was recrystallized from methanol to provide 230 g. of the desired compound of a melting point of 80° to 82° C.
Reaction SMILES: [N+:1]([C:4]1[C:16]2[C:15]3[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][C:14]=3[N+:17]([O-:19])=[O:18])[C:9](=[O:23])[C:8]=2[CH:7]=[C:6]([C:24]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])=[O:25])[CH:5]=1)([O-:3])=[O:2].[CH2:39](N(CC)CC)C.[CH2:46]1C[O:49][CH2:48][CH2:47]1>>[N+:1]([C:4]1[C:16]2[C:15]3[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][C:14]=3[N+:17]([O-:19])=[O:18])[C:9](=[O:23])[C:8]=2[CH:7]=[C:6]([C:24]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:38][C:48](=[O:49])[C:47]([CH3:46])=[CH2:39])=[O:25])[CH:5]=1)([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: O=C(OCCOCCOCCOCCO)c1cc2c(c([N+](=O)[O-])c1)-c1c(cc([N+](=O)[O-])cc1[N+](=O)[O-])C2=O
Reactant: C1CCOC1
Product: C=C(C)C(=O)OCCOCCOCCOCCOC(=O)c1cc2c(c([N+](=O)[O-])c1)-c1c(cc([N+](=O)[O-])cc1[N+](=O)[O-])C2=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
0.7 g (1.3 mmol) 22, 0.15 g (1.44 mmol) 19 and 0.5 g activated molecular sieves (4 Å) were added to dry THF (10 ml). After the mixture was cooled to 0° C., 0.15 g (1.44 mmol) triethylamine was added. Then it was allowed to reach room temperature and was stirred for three hours. Ammonium salts were filtered off, the THF was evaporated and the crude product was redissolved in chloroform. The solution was extracted three times with diluted potassium hydroxide solution, two times with water, one time with brine and was then dried over magnesium sulfate. After the chloroform was evaporated, the monomer was purified by column chromatography on silica gel using 50% ethyl acetate in hexanes as eluent. The evaporation of the solvent yielded 0.4 g (51%) of a viscous dark orange oil. Rf=0.37 (EtOAc/hexanes: 1/1). 1H NMR (CDCl3, 500 MHz, 20° C.): d 8.99 (s, 1H), 8.85 (m, 2H), 8.74 (s, 1H), 6.10 (s, 1H), 5.56 (s, 1H), 4.60 (m, 2H), 4.28 (m, 2H), 3.88 (m, 2H), 3.71 (m, 10H), 1.93 (s, 3H). 13C NMR (CDCl3, 125 MHz, 20° C.): d 184.9, 162.6, 149.6, 146.8, 138.5, 138.4, 137.6, 136.2, 136.1, 135.5, 131.7, 129.3, 125.7, 125.3, 122.6, 70.7, 69.1, 68.8, 65.7, 63.8, 18.3.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][CH2:32][OH:33])[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][CH2:32][OH:33])=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Reactant: CCNCCO
Product: CCN(CCO)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with 2-ethylamino-ethanol
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]>>[Cl:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]3)[CH:22]=2)[CH:34]=[C:33]([F:46])[C:32]=1[OH:47]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 73.7 %

Procedure:
Following general procedure F, {6-Bromo-4-[1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-ylamino]quinolin-3-yl}(cyclopropyl)methanone (58 mg, 0.120 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (49 mg, 0.180 mmol) to afford the desired product (46 mg, 74%) as a yellow-green solid: 1H NMR (500 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.08 (s, 1H), 8.24 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.8, 2.1 Hz, 1H), 7.93-7.83 (m, 2H), 7.43 (s, 1H), 7.39-7.30 (m, 2H), 4.19-4.12 (m, 1H), 2.95-2.81 (m, 3H), 2.29-2.15 (s, 5H), 2.01-1.89 (m, 4H), 1.02-0.92 (m, 4H).; ESI MS m/z 520 [C28H27ClFN5O2+H]+; HPLC 98.6% (AUC), tR=10.16 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:19][CH2:18]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C([C:57](OC)=[O:58])#N>O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]4([CH2:57][OH:58])[CH2:18][CH2:19][N:20]([C:23]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:21][CH2:22]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:3][CH2:2]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Reactant: COC(=O)C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C3(CO)CCN(C(c4ccccc4)(c4ccccc4)c4ccccc4)CC3)ccc2n1CC1CC1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-neopentyl-5-(1-tritylpiperidin-4-ylsulfonyl)-1H-benzo[d]imidazole (STEP E, 2.05 g, 3.24 mmol) in tetrahydrofuran (60 mL) at −60° C. was added lithium diisopropylamide (1.8 mol/L heptane/tetrahydrofuran/ethylbenzene solution, 2.34 mL, 4.22 mmol). After the mixture was warmed up to −40° C. over a period of 20 min and then stirred for 40 min at the same temperature, methyl cyanoformate (828 mg, 9.73 mmol) in tetrahydrofuran (3 mL) was added to the mixture. The mixture was stirred at 0° C. for 1.5 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (dichloromethane-ethyl acetate, gradient) to give 4:1 mixture of the title compound and the starting material (2.15 g).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:22]([NH:24][CH2:25][CH3:26])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH2:22]([N:24]([CH2:25][CH3:26])[C:2]1[CH:3]=[CH:4][C:5]([N+:19]([O-:21])=[O:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH:7]=1)[CH3:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1-c1ccc(OC(F)(F)F)cc1
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCN(CC)c1ccc([N+](=O)[O-])c(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 70.6 %

Procedure:
A mixture of 5-fluoro-2-nitro-4′-(trifluoromethoxy)biphenyl (compound of Example 78(1)) (700 mg, 2.32 mmol), diethylamine (339 mg, 4.64 mmol), potassium carbonate (320 mg, 2.32 mmol) and acetonitrile (5 ml) was stirred at 100° for 10 hours under argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1) to give the title compound (580 mg, 70.5%) as a yellow solid.
Reaction SMILES: [CH:1]1([NH2+]C2CCCCC2)CCCCC1.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1)[C:23]([O-:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].O[Li].O.COS(OC)(=O)=O.C(C)(C)C.C(OC(C)(C)C)=O>C1COCC1>[CH3:1][O:24][C:23](=[O:25])[C@@H:22]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:20])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([Cl:34])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(Cl)c1)C(=O)[O-]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(C)OC=O
Agent: CC(C)C
Agent: [Li]O
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(O)c(Cl)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 10 mL round-bottomed flask, (S)-2-(tert-butoxycarbonylamino)-3-(3-chloro-4-hydroxyphenyl)propanoate dicyclohexylammonium salt (300 mg, 604 μmol, Eq: 1.00) was combined with dry THF (2 mL) to give a white suspension. LiOH hydrate (38.4 mg, 905 μmol, Eq: 1.50) was added and the mixture was stirred for 30 min at 25° C. Then Me2SO4 (80.1 mg, 60.7 μL, 604 μmol, Eq: 1.00) was added. The reaction mixture was heated to 80° C. and stirred for 2 h. After that the mixture was stirred for 18 h at 50° C. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with AcOEt (2×). The organic layers were combined and washed with brine (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, n-heptane/AcOEt 4/1, 3/1) to yield a colorless oil (132 mg; 66%). m/z=330.2 [M+H]+; 274.1 [M+H-tBu]+; 230.2 [M+H-Boc]+.
Reaction SMILES: [F-:1].[Na+].[F:3][C:4](F)([F:15])[O:5][C:6](F)(F)[C:7](F)(F)[C:8](F)=[O:9].[CH3:17][OH:18]>>[CH3:17][O:18][C:8](=[O:9])[CH2:7][CH2:6][O:5][C:4]([F:15])([F:3])[F:1]
Reactant: O=C(F)C(F)(F)C(F)(F)OC(F)(F)F
Reactant: [F-]
Reactant: CO
Agent: [Na+]
Product: COC(=O)CCOC(F)(F)F
Yield: 129.2 %

Procedure:
A 5-L round bottom 3-neck flask equipped with a −78° C. condenser and mechanical stirred was charged with 1025 g of methanol and 300 g of sodium fluoride. 3-Trifluoromethoxytetrafluoropropionyl fluoride (1561 g, 6.7 mol), prepared as described in Example 1 of U.S. Pat. No. 6,482,979 (Hintzer et al.), was added to the flask at −20° C. The reaction mixture was washed with 800 g water and phased split to give 1490 g of methyl-3-trifluoromethoxypropionate for a 91% yield after fractionation. A 5-liter round bottom flask equipped with a mechanical stirrer, a −78° C. condenser and addition funnel was charged with 1463 g of methyl-3-trifluoromethoxypropionate (6 mol) and 940 g of dimethylformamide. The mixture was stirred at room temperature and 125 g of ammonia (7.4 mol) was added to convert the ester to amide. Methanol was vacuum stripped and 1160 g of pyridine (14.7 mol) was added. The mixture was cooled to −14° C. and 1493 g of trifluoroacetic anhydride (7.1 mol) was added. After addition was completed, 1 kg of water was added and the product began to reflux on the condenser. A total of 1165 g of heptafluoro-3-methoxypropanenitrile, CF3OCF2CF2CN was obtained after distillation.
Reaction SMILES: [CH2:1]1C2[C:5](=[CH:6][CH:7]=[CH:8]C=2)[CH:4]=[CH:3][CH2:2]1.[Br:11]N1C(=O)CCC1=O.CC[O:21][CH2:22][CH3:23]>O.O1CCCC1>[Br:11][C@@H:1]1[CH2:2][CH2:3][C:4]2[C:23](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@H:22]1[OH:21]
Reactant: C1=Cc2ccccc2CC1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O[C@@H]1c2ccccc2CC[C@H]1Br
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 13.0 g (100 mmol) of dihydronaphthalene, dissolved in a mixture of 100 ml of water and 400 ml of tetrahydrofuran, at ambient temperature, there are added, all at once, 19.6 g (110 mmol) of N-bromosuccinimide and stirring is carried out for 3 hours. There are then added 200 ml of ice-cold water and 200 ml of ether; stirring is carried out and the phases are separated. The aqueous phase is extracted with 200 ml of ether; the combined organic phases are then washed with 200 ml of a saturated aqueous solution of sodium chloride and dried and then evaporated to yield the expected compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([S:18][CH3:19])=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[S:15][CH3:16].[CH2:20]1C[O:23][CH2:22][CH2:21]1>O>[CH3:19][S:18][C:10]1[C:9]([NH:8][C:22](=[O:23])[CH:21]=[CH2:20])=[C:14]([S:15][CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: C1CCOC1
Reactant: CSc1cc(C)nc(SC)c1N
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)Nc1c(SC)cc(C)nc1SC
Reaction time: 14 h
Yield: 44 %

Procedure:
Triethylamine (277 mg, 2.75 mmol) was added to a solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (500 mg, 2.50 mmol) in THF (10 ml), then a solution of acryloyl acid chloride (225 mg, 2.50 mmol) in THF (3 ml) was gradually dropped thereinto and the mixture was stirred for 14 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated therefrom and the resulting crystals were recrystallized from chloroform-ethyl acetate-hexane to provide 276 mg (yield 44%) of N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acrylamide as colorless powdery crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35][CH2:34]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:41][CH2:40][CH:36]([C:37]([OH:39])=[O:38])[CH2:35][CH2:34]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: O=C(O)C1CCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(C(=O)O)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with isonipecotic acid. A yellow solid 106 was obtained (0.0225 g, 47%). 1H-NMR (CDCl3, 400 MHz) δ 1.90-1.99 (m, 2H), 2.09-2.16 (m, 2H), 2.68-2.77 (m, 1H), 3.43-3.50 (m, 2H), 3.83 (s, 3H), 4.14-4.20 (m, 2H), 6.95 (d, J=6.2 Hz, 1H), 6.99-7.05 (m, 3H), 7.06 (d, J=8.4 Hz, 1H), 7.45-7.52 (m, 3H), 7.84 (s, 1H), 8.20 (d, J=6.6 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[C:12]4[CH:24]=[CH:23][CH:22]=[N:21][C:13]=4[NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:25]2[CH:30]=[CH:29][C:28]([C:31]3([NH:35]C(=O)OC(C)(C)C)[CH2:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:43]>ClCCl.O1CCOCC1.CCOCC>[ClH:43].[C:1]1([C:7]2[N:11]3[C:12]4[CH:24]=[CH:23][CH:22]=[N:21][C:13]=4[NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:25]2[CH:26]=[CH:27][C:28]([C:31]3([NH2:35])[CH2:34][CH2:33][CH2:32]3)=[CH:29][CH:30]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4n(c3-c3ccccc3)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: NC1(c2ccc(-c3nc4n(c3-c3ccccc3)-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (1-(4-(3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutyl)carbamate (0.028 g) in dichloromethane (5 mL) was added 4.0 M HCl in dioxane (0.5 mL). The reaction was stirred at room temperature for 6 hours and then diluted with ether (20 mL). The product was removed by filtration under reduced pressure and dried to give 1-(4-(3-phenyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)phenyl)cyclobutanamine hydrochloride as a white solid (0.022 g, 77% based on tris HCl salt). M.p.: 252-258° C.; 1H NMR (DMSO-d6) 400 MHz δ 8.78 (br. s, 3 H), 8.73 (br. s, 1H), 8.11 (dd, JA=4.8 Hz, JB=1.2 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.47-7.38 (m, 4H), 7.32 (d, J=8.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.17 (t, J=7.6 Hz, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.77 (dd, JA=7.6 Hz, JB=4.8 Hz, 1H), 2.60-2.52 (m, 4H), 2.24-2.13 (m, 1H), 1.85-1.72 (m, 1H); LCMS: 456 [M+H]; Calc. for C30H25N5.3.86HCl.0.48 diethylether: C, 60.68; H, 5.37; N, 11.08. Found C, 60.68; H, 5.52; N 11.08.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]=[CH:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH2:27][C:20]5=[N:19][C:18]=4[CH3:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1C=CN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a suspension of 1.39 g (3,42 mmoles) of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-vinyl}-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one (III) in 22 mL of absolute ethanol and 1 mL of glacial acetic acid under stirring at room temperature and in a protective atmosphere, 0.254 g (4.04 mmoles) of sodium cyanoborohydride in small portions was added for 1 hour. After 1.5 hour, the solvent was evaporated and the crude product obtained was dissolved in 250 mL of ethyl acetate. The organic phase was successively washed with 50 mL of 1M aqueous sodium bicarbonate solution, 50 mL of water and 50 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulphate. The resultant solution was filtered and the solvent was evaporated to yield 1.17 g of a residual solid (83%), which was diluted in methylene chloride and purified by column chromatography (silica gel). Elution of the column was with methylene chloride, methanol and triethylamine (95:5:1). The pure fractions were collected and the solvent was evaporated under reduced pressure to give 0.83 g (70.9%) of 3-{2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-4-one (I). Optionally, the reaction crude product was purified by crystallization from a suitable organic solvent, preferably ethanol or 4-methyl-2-pentanone.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].N1CCCCC1.Cl>CN(C)C=O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[C:16]1[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:14][C:15]1=[O:23])[CH2:7][CH2:6]2
Reactant: CN(C)c1ccc2c(c1)CCC2=O
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CN(C)c1ccc2c(c1)CCC2=C1C(=O)Nc2ccccc21
Temperature: 130 °C
Yield: 4.2 %

Procedure:
A mixture of 0.5 g 5-dimethylamino-1-indanone, 1.1 g oxindole and 2.5 ml piperidine in 4 ml dimethylforamide was heated in a sealed tube at 130° C. for 12 hours to yield a reddish-black suspension. The mixture was added to 1N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried with magnesium sulfate and concentrated. Chromatography afforded 35 mg of 3-(5-dimethylamino-indan-1-ylidene)-1,3-dihydroindol-2-one as a brown solid.