Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH3:16])[N+:12]([O-])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:23])C.CO>C(O)(=O)C>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:16][OH:23])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Cc1cc(OCc2ccc(C(F)(F)F)cc2)cc[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: OCc1cc(OCc2ccc(C(F)(F)F)cc2)ccn1
Temperature: 80 °C

Procedure:
3.4 g (12 mmol) of the title compound from Example 2 are warmed to 80° C. in 5 ml of glacial acetic acid and 10 ml of acetic anhydride are added dropwise at this temperature with stirring. The mixture is then warmed to 110°-120° C. for 2 hours, allowed to cool to 80° C., 10 ml of methanol are added, the mixture is heated to reflux for a further 15 minutes and subsequently concentrated. The residue is taken up in 10 ml of methanol and rapidly added dropwise at 10° C. to 50 ml of 2N methanolic NaOH. The solution is then clarified over charcoal, concentrated, the residue treated with 50 ml, extracted three times using 50 ml of dichloromethane, and the organic phase dried and concentrated. The crystallized residue is triturated with a petroleum ether/diisopropyl ether mixture (1:1), and the product is filtered off with suction, washed with a little diisopropyl ether and dried in vacuo, m.p. 96°-98° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16].O1CC1>CCO>[CH2:15]([N:17]([CH2:18][CH3:19])[CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]1[CH:13]=[CH:14][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:16]
Reactant: CCNCC
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Solvent: CCO
Solvent: C1CO1
Product: CCN(CC)CC(O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of 2-(4-nitro-phenoxymethyl)-oxirane (9.75 g, 50 mmol) in absolute EtOH (100 mL) was heated at 70° C. until 2-(4-nitro-phenoxymethyl)-oxirane is dissolved then the solution was allowed to cool to room temperature. Subsequently the room temperature solution was treated with diethylamine (5.2 mL, 1.0 equiv.) in one portion. The reaction mixture is stirred at room temperature for 15 min during which time starting material (oxirane) began to precipitate out of solution. The reaction mixture was heated to 50° C. and an additional amount of diethylamine (2.6 mL) was added to achieve complete dissolution of starting oxirane. The reaction mixture was heated for an additional 5 h at 55° C. at which point thin layer chromatography (9:1, chloroform:methanol) indicated complete consumption of the starting oxirane. The reaction mixture was cooled to room temperature and concentrated in vacuo. The oily light brown residue obtained after evaporation, was purified by flash silica gel chromatography, (CHCl3 to 1:9, MeOH:CHCl3 gradient eluant) to give the 1-diethylamino-3-(4-nitro-phenoxy)-propan-2-ol as a yellow oil (11.9 g, 89%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC(C)(C)CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, off-white solid (98 mg, 92%), MS (ISP) m/z=429.4 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 3,3-dimethyl-butanoic acid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CS(O[CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])(=O)=O>CN(C=O)C>[CH3:13][C:5]([CH3:14])([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:4][O:3][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41]
Reactant: COCCOCCOCCOCCOCCOCCOCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCCOCCOCCOCC(C)(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 48 %

Procedure:
Sodium hydride (60% wt in oil) (400 mg, 10 mmol) was added to a stirred solution of tert-butyl 3-hydroxy-2,2-dimethylpropanoate (57) (1.74 g, 10 mmol) in DMF (20 mL) at 0° C., after 30 min a solution of 2,5,8,11,14,17,20-heptaoxadocosan-22-yl methanesulfonate (2.79 g, 6.67 mmol) in DMF (10 mL) was added dropwise, and the reaction mixture was allowed to warm to RT and stirred for 16 h. The reaction was quenched with water (100 mL) and the aqueous layer was extracted with DCM (2×100 mL), the combined organic layers were washed with brine (3×100 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (120 g, 0-10% MeOH in EtOAc) to afford tert-butyl 25,25-dimethyl-2,5,8,11,14,17,20,23-octaoxahexacosan-26-oate (58) (1.59 g, 48%) as a colourless oil: 1H NMR (400 MHz, CDCl3) δ: 3.65-3.51 (m, 32H), 3.40 (s, 2H), 3.36 (s, 3H), 1.41 (s, 9H), 1.11 (s, 6H).
Reaction SMILES: C([C:5]1[N:6]([C:20](=[O:28])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:7]2[C:12]([C:13]=1[CH2:14][C:15]([O-:17])=[O:16])=[CH:11][CH:10]=[C:9]([O:18][CH3:19])[CH:8]=2)(C)(C)C>C1C=CC=CC=1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([O:18][CH3:19])[CH:8]=3)[C:13]([CH2:14][C:15]([OH:17])=[O:16])=[CH:5]2)=[O:28])=[CH:22][CH:23]=1
Reactant: COc1ccc2c(CC(=O)[O-])c(C(C)(C)C)n(C(=O)c3ccc(Cl)cc3)c2c1
Solvent: c1ccccc1
Product: COc1ccc2c(CC(=O)O)cn(C(=O)c3ccc(Cl)cc3)c2c1
Temperature: 210 °C

Procedure:
A mixture of 1.0 g. of the ester obtained in step C and 0.1 powdered porous plate is heated, with stirring, in an oil bath at 210° C. under nitrogen, then dissolved in benzene and ether, filtered and extracted with sodium bicarbonate solution. The aqueous solution is filtered by suction to remove ether, neutralized with acetic acid, then acidified weakly with dilute hydrochloric acid. The crude product is then recrystallized from aqueous ethanol and dried in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:18]([OH:21])[CH2:19][Br:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O-])=O.C1COCC1>C1(C)C=CC=CC=1>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:18]([OH:21])[CH2:19][Br:20])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc([C@H](O)CBr)ccc1OCc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Nc1cc([C@H](O)CBr)ccc1OCc1ccccc1
Yield: 69.6 %

Procedure:
A solution of the product of step A) (18.7 g, 53.1 mmol) in toluene (40 mL) and THF (40 mL) was added to a Parr shaker bottle containing Pt2O (370 mg). This mixture was shaken under H2 (50 psi, 344.74 kpa) until the reaction was complete (18 h). The catalyst was removed by filtration, and the filtrate was concentrated to an oil. Column chromatography (1 kg silica gel packed in and eluted with CH2Cl2/MeOH, 19:1) gave 11.9 g (69.6%) of the title compound.
Reaction SMILES: C(#N)C.[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=O)[CH2:18][C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH2:29]([NH:31][NH2:32])[CH3:30]>O>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:31]([CH2:29][CH3:30])[N:32]=[C:19]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Reactant: CCNN
Solvent: CC#N
Solvent: O
Product: CCn1nc(Cc2ccccc2)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 19 °C
Reaction time: 1 h

Procedure:
A 100 L cylindrical flask with a bottom valve was equipped with a mechanical stirrer, internal heating coil, 5 L dropping funnel, and thermocouple was charged with the acetonitrile (39 L) and 1-(1-(t-butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione 4 (3.00 Kg, 8.68 mol). To the resulting clear light yellow solution was added water (18.6 l). The mixture was warmed to 19° C. and the mixture became clear. An ethyl hydrazine solution (35% in water, 1.66 Kg, 1.71 L, 9.55 mol) was added via a dropping funnel over 100 min. The batch temperature after the addition was 20° C. The reaction solution was aged for 1 h at 20 □ C then checked for completion by HPLC. If any 4 remained, additional ethyl hydrazine was added to complete the reaction. At the end of reaction the ratio of products 5:6:7 is 83.6:14.3:2.1 with complete consumption of 4.
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]1([CH3:35])[CH:15]=[CH:14][C:13]([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]#[N:29])=[CH:25][CH:26]=3)[C:21]([CH:30]3[CH2:32][CH:31]3[CH:33]=[CH2:34])=[CH:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[OH-:36].[Na+].OO>C1COCC1.C(O)C>[OH:36][CH2:34][CH2:33][CH:31]1[CH2:32][CH:30]1[C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[N:19]([S:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:35])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH:20]=1
Reactant: [OH-]
Reactant: C=CC1CC1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3CC3CCO)c3cc(C#N)ccc32)cc1
Temperature: 30 °C
Yield: 45 %

Procedure:
9-Borabicyclo[3.3.1]nonane (4.1 ml of 0.5 M THF solution, 2.05 mmol) was added drop wise under a nitrogen atmosphere to a stirred solution of 1-(toluene-4-sulfonyl)-3-(2-vinyl-cyclopropyl)-1H-indole-5-carbonitrile (735 mg, 2.01 mmol) in dry THF (6 ml). The solution was heated to 30° C. for 6 hr and then cooled to 20° C. Absolute ethanol (12 ml), sodium hydroxide (2.6 ml of a 1N solution, 2.6 mmol), and hydrogen peroxide (0.85 ml of a 30% solution) were added sequentially to the stirred solution. The mixture was heated to 40° C. for 1 hr and then cooled to room temperature. Sodium hydroxide (2 ml of a 1N solution) was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using 3% acetone in methylene chloride as the eluent to give 3-[2-(2-hydroxy-ethyl)-cyclopropyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (300 mg, 45%). 1H NMR (300 MHz, CDCl3): δ8.01 (d, 2H), 7.97 (s, 1H), 7.73 (d, 1H), 7.28 (s, 1H), 7.24 (d, 2H), 3.80 (m, 2H), 2.35 (s, 3H), 1.74-1.62 (m, 4H), 1.08 (m, 1H), 0.90 (m, 1H), 0.83 (m, 1H). MS m/e 381.17 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11]1)=[O:9].F[B-](F)(F)F.C([O+](CC)CC)C.[N:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][NH2:38])=O)=[N:31][CH:30]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][N:13]2[C:35]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][N:31]=3)=[N:37][N:38]=[C:12]2[CH2:11]1)=[O:9]
Reactant: NNC(=O)c1ccncn1
Reactant: O=C1CN(C(=O)c2ccccc2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: O=C(c1ccccc1Cl)N1CCn2c(nnc2-c2ccncn2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in a method analogous to the example E111. To a solution of 4-[(2-chlorophenyl)carbonyl]-2-piperazinone (I4) (269 mg, 1.127 mmol,) in Dichloromethane (5 ml) stirred under argon at room temp was added solid triethyloxonium tetrafluoroborate (214 mg, 1.127 mmol). The reaction mixture was stirred at RT for 1 hr. Solid 4-pyrimidinecarbohydrazide (I71 mg, 1.240 mmol, commerically available from e.g. Anichem, J&W PharmLab or Bepharm) was added and the reaction mixture stirred at RT for 18 hr. The solvent was evaporated in vacuo, and the residue dissolved in n-butanol (5 ml) and stirred at 120° C. for 3 hr. The reaction mixture was cooled to room temperature and partitioned between Dichloromethane (˜50 ml) and saturated brine (˜25 ml). The aqueous phase was extracted with Dichloromethane (2×25 ml) and the combined organic extracts washed with saturated brine (2×25 ml), dried over sodium sulphate and evaporated in vacuo to afford the crude product (−Z1) as a dark orange oil. This was dissolved in 1:1 MeOH:DMSO and purified by Open Access Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier. The solvent was evaporated in vacuo, and the residue washed with ether (˜10 ml) and dried overnight in a vacuum oven at 40° C. to afford the required product as a yellow solid in 74.1 mg.
Reaction SMILES: [CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH:24]=O)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>>[CH2:1]([O:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][NH:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C=O)c2ccccc12
Product: CCCCCCCCCCCCOc1ccc(CNCc2ccc(C(F)(F)F)cc2)c2ccccc12
Yield: 66 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(dodecyloxy)-1-naphthaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (66%). 1H NMR (CDCl3, 300 MHz) δ 8.20 (d, J=7.9 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.76-7.41 (m, 6H), 7.32 (d, J=7.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 4.19-4.11 (m, 4H), 3.63 (s, 2H), 1.96-1.84 (m, 2H), 1.63-1.47 (m, 2H), 1.45-1.20 (m, 16H), 0.87 (t, J=6.8 Hz, 3H). HPLC (Condition A), Rt: 5.41 min (HPLC purity: 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH:27]1[CH2:29][O:28]1>>[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[O:25][CH2:26][CH:27]([OH:28])[CH2:29][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: Clc1ccccc1OCC1CO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccccc3Cl)CC1)O2

Procedure:
Compound 172 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-[(2-chlorophenoxy)methyl]oxirane and conditions outlined in procedure X. LCMS: 486 [M+H]; Rt=1.04 min.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][OH:24].Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>C1(C)C=CC=CC=1>[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][O:24][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)CBr
Reactant: OCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)COCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
0.478 g of a 55% w/w dispersing of sodium hydride in mineral oil was added to a solution of 1.5 g of 2-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepin-2-yl)ethanol [prepared as described in step (a) or (c) above] dissolved in 20 ml of toluene, under an atmosphere of nitrogen. The mixture was then stirred at 40° C. for 2 hours, after which 0.924 g of methyl bromoacetate was added, whilst ice-cooling; the mixture was then stirred at 40° C. for a further 4 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to afford 0.58 g (31% yield) of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[N:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1)[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].O.Cl.O>C1COCC1.CO>[C:1]([O:5][CH:6]([C:11]1[N:12]([CH3:32])[C:13](=[O:31])[C:14]2[C:19]([C:20]=1[N:21]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH3:30])[CH:24]=1)[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(N(C)c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(N(C)c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3ccccc23)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.4 %

Procedure:
To a mixture of methyl 2-(4-((3,4-dimethylphenyl)(methyl)amino)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-hydroxyacetate (90 mg, 0.237 mmol) and amberlyst 15 resin (45 mg, 0.237 mmol) in DCM (3 mL) at −70° C. was bubbled a stream of isobutylene until the volume doubles. The tube was sealed, and the reaction was stirred at room temperature for 10 hours. The mixture was filtered through a short pad of silica gel, washed with DCM and EtOAc, and the filtrate was concentrated. The mixture was purified on silica using EtOAc/hexanes 0-40% to give the intermediate methyl ester as an off-white solid (41.6 mg, 39%). 1H NMR (400 MHz, CDCl3) δ ppm 8.56-8.44 (m, 1 H), 7.59-7.42 (m, 3 H), 7.26-7.14 (m, 1 H), 7.05-6.93 (m, 1 H), 6.03-5.82 (m, 2 H), 3.74-3.67 (m, 7 H), 3.33 (s, 4 H), 2.23-2.12 (m, 6 H), 1.38-1.22 (m, 4 H), 1.12-1.00 (m, 9 H); ES-LCMS: 437.4 (M+1). To a solution of methyl 2-(tert-butoxy)-2-(4-((3,4-dimethylphenyl)(methyl)amino)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)acetate (41.6 mg) in THF (3.0 mL) and MeOH (1 mL) was added a solution of LiOH/water (1.183 mL, 1.183 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and 1N HCl/water was added to pH˜3 and the mixture was purified by reverse phase HPLC on a C18 column using MeCN/water 10-90% containing 0.05% TFA to provide the title compound as an off-white solid (19.5 mg, 19%). 1H NMR (400 MHz, CDCl3) ppm 8.58-8.42 (m, 1 H), 7.62-7.45 (m, 2 H), 7.21-7.12 (m, 1 H), 7.02-6.58 (m, 2 H), 6.02 (s, 1 H), 3.79-3.63 (m, 3 H), 3.41 (s, 3 H), 2.30-2.07 (m, 6 H), 1.27-1.08 (m, 9 H); ES-LCMS: 423.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[O:12][CH2:14][CH:15]1[CH2:17][CH2:16]1
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: BrCC1CC1
Product: FC(F)(F)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from commercially available 2-bromo-4-trifluoromethyl-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:20]([CH3:22])[CH:21]=2)=[CH:13][C:12]=1[C:29]([F:32])([F:31])[F:30].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[N:6][C:7]=1[N:26]1[CH2:27][CH2:28][CH:23]([C:19]2[N:20]([CH3:22])[CH:21]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([F:10])=[C:12]([C:29]([F:32])([F:30])[F:31])[CH:13]=3)[N:18]=2)[CH2:24][CH2:25]1
Reactant: Nc1ncnc(Cl)c1Br
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A mixture of 5-bromo-6-chloropyrimidin-4-amine (357.2 mg; 1.71 mmol; 1.02 eq.), 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine (550.00 mg; 1.68 mmol; 1.0 eq.), potassium carbonate (464.4 mg; 3.36 mmol; 2.0 eq.) in DMSO (6.0 ml) was stirred at 60° C. overnight. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 86% yield. LC-MS: (M+1=499, obsd.=499).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[N:31][N:32]([CH:34]([CH3:36])[CH3:35])[CH:33]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH:34]([N:32]1[CH:33]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:20]3([C:17]4[N:13]5[CH2:14][CH2:15][S:16][C:10]([CH2:9][OH:8])([CH3:37])[CH2:11][C:12]5=[N:19][N:18]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH:30]=[N:31]1)([CH3:36])[CH3:35]
Reactant: CC(C)n1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Agent: Cl
Solvent: CO
Product: CC(C)n1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)cn1
Yield: 119.8 %

Procedure:
A solution of the compound (217 mg, 0.40 mmol) obtained in Example 75-1) and 4 M hydrochloric acid (1,4-dioxane solution, 2 mL) in methanol (8 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (203 mg, quant.) as a colorless solid.
Reaction SMILES: C(O)C.C1N2CN3CN(C2)C[N:5]1C3.N.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=O)=[O:18]>C(Cl)(Cl)Cl>[C:24]1([C:22]2[C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]=3[NH:19][C:17](=[O:18])[CH2:16][N:5]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCl)Nc1ccccc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1
Reaction time: 3 h
Yield: 84.6 %

Procedure:
A mixture of ethanol (300 ml) and hexamethylenetetramine (20 g., 0.143 mol) was stirred, heated to reflux, and saturated with ammonia. 2-Chloroacetamidobenzophenone (18.1 g., 0.066 mol) was added in small increments over 3 to 4 hours while a steady stream of ammonia was bubbled into the reaction mixture. Refluxing was continued for 3 hours after complete addition of 2-chloroacetamidobenzophenone. The flow of ammonia was interrupted and the ethanol removed by distillation in vacuo. The residue obtained was taken up in chloroform (200 ml), and washed with water (100 ml) at 50° C. The chloroform layer was evaporated to dryness at 30° C. and the oily solid obtained was recrystallized from toluene (100 ml) to give 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (13.2 g., 86%), melting at 184°-186° C.