Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[I:28])=[O:6].[Cl:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[Cl:32][C:33]1[N:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35]([NH:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[C:13]([C:14]([F:16])([F:17])[F:15])=[CH:12][C:11]([C:18]([F:27])([C:19]([F:20])([F:21])[F:22])[C:23]([F:24])([F:25])[F:26])=[CH:10][C:9]=2[I:28])[CH:3]=1)=[O:36]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1cccc(C(=O)Nc2c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc(NC(=O)c2cccnc2Cl)c1

Procedure:
According to the method of 1-7 of Example 1, a target compound was prepared from 3-amino-N-(2-iodo-4-(perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)benzamide and 2-chloronicotinoylchloride.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[N:5]=1.[Li]CCCC.CN([CH:24]=[O:25])C.C([O-])(O)=O.[Na+]>CCOCC.CCCCCC>[CH3:15][C:10]1([C:6]2[N:5]=[C:4]([CH:24]=[O:25])[CH:9]=[CH:8][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CN(C)C=O
Reactant: CC1(c2cccc(Br)n2)OCCO1
Agent: N#N
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(c2cccc(C=O)n2)OCCO1
Temperature: 25 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2-bromo-6-(2-methyl-[1,3]dioxolan-2-yl)-pyridine (2.21 g, 9.05 mmol) in Et2O (60.0 mL) at −78° C. was added dropwise n-BuLi (3.70 mL of a 2.5M solution in hexane, 9.25 mmol). The reaction mixture was then stirred at −78° C. for 30 min before DMF (0.85 mL, 11.00 mmol) was added dropwise. The reaction mixture was allowed to warm to rt over 1 h. 5% aq. NaHCO3 was added and the mixture was extracted three times with Et2O. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA to pure EA) gave the title compound as a pale yellow solid.
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]2[CH:11]3C[CH:14]([C:7]=2[S:6]1(=[O:17])=[O:16])[CH2:13][CH2:12]3)(C)(C)C>FC(F)(F)C(O)=O>[S:6]1([C:7]2[C:8](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:10])[NH:5]1)(=[O:16])=[O:17]
Reactant: CC(C)(C)N1C(=O)C2=C(C3CCC2C3)S1(=O)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NS(=O)(=O)c2ccccc21
Reaction time: 96 h

Procedure:
The 2-t-butyl-4,5,6,7-tetrahydro-4,7-methano-1,2-benzisothiazol-3(2H)one 1,1-dioxide (2.8 g, 0.011 mol) in trifluoroacetic acid (30 mL) was heated at reflux for 48 hr and let stand at room temperature for 4 days. The resulting mixture was concentrated in vacuo, treated with methanol (20 mL) and evaporated to dryness. The residue was taken up in ether (100 mL) and washed with saturated NaHCO3 (1×50 mL). The layers were separated, the aqueous phase acidified to pH 1 with 2N HCl and extracted with MDC (2×100 mL). The combined organic extracts were dried and concentrated in vacuo to give 0.9 g (42%) of the bicyclo (2.2.1) saccharin derivative as a white solid.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH:35]=O)([O-:31])=[O:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=[N+]([O-])c1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 3-nitrobenzaldehyde. MS (ESI) m/z 512.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH:7]=[CH:8][CH:9]=1)C=O.CO[CH:14]([O:17][CH3:18])[O:15][CH3:16].ClS(O)(=O)=O>CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:14]([O:15][CH3:16])[O:17][CH3:18])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Br)cccc1C=O
Reactant: COC(OC)OC
Agent: O=S(=O)(O)Cl
Solvent: CO
Product: COc1c(Br)cccc1C(OC)OC
Reaction time: 3 h
Yield: 81 %

Procedure:
3-Bromo-2-methoxybenzaldehyde (28 g, 130 mmol) was combined with trimethylorthoformate (27.5 g, 28.6 mL, 260 mmol) in methanol (150 mL) and then chlorosulfonic acid (0.5 mL) was added dropwise to the mixture. The mixture was stirred for 3 hours and then concentrated by rotoevaporation. The residue was partitioned between ethyl ether and 5% aqueous sodium bicarbonate and the organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated to give 1-bromo-3-dimethoxymethyl-2-methoxybenzene (27.5 g).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:28])[CH3:27]>C(#N)C>[F:1][C:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1([OH:18])[CH2:17][CH2:16][N:15]([CH:26]([CH3:28])[CH3:27])[CH2:14][CH2:13]1
Reactant: OC1(c2cccc(C(F)(F)F)c2F)CCNCC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CCC(O)(c2cccc(C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 2: 4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidin-4-ol (0.02 g, 0.076 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 2-bromopropane (0.008 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 305 (M+, 5), 290 (79), 191 (30), 163 (18), 56 (bp).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]3C(=O)C4=CC=CC=C4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=O.O.NN>C(O)C>[CH3:39][N:37]([CH3:38])[CH2:36][CH2:35][C:19]1[N:18]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=3[C:7]([C:9]3[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=3[F:15])=[N:24][CH2:23][C:22]2=[N:21][N:20]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 1C, 5-chloro-2',6'-difluoro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine hydrate to give 1-[2-(dimethylamino)ethyl]-8-chloro-6-(2,6-difluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine. This compound is converted to its hydrochloride by treating it with ethereal hydrogen chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([C:11](=O)[NH2:12])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:27][C:28]1[CH:29]=[C:30]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:31](N)=[CH:32][CH:33]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]([C:11]1[N:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:29]=[C:28]([F:27])[CH:33]=[CH:32][C:31]=2[N:12]=1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(F)cc1Nc1ccccc1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
To a suspension of ((S)-1-carbamoylpropyl)carbamic acid tert-butyl ester (300 mg, 1.48 mmol) in DCM (5 mL) was added triethyloxonium tetrafluoroborate (273 mg, 1.43 mmol) and the reaction mixture stirred at RT for 1.5 h under argon. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in ethanol (3 mL). 4-Fluoro-N2-phenylbenzene-1,2-diamine (97 mg, 0.48 mmol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, and the resulting residue partitioned between DCM and sat. NaHCO3. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—PPC, gradient 0-20% EtOAc in cyclohexane) to afford the title compound as a pink foam (96 mg, 54%). LCMS (Method J): RT=3.70 min, [M+H]+=370.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(Oc2ccccc2)c1
Yield: 96.4 %

Procedure:
A mixture 4-methoxy-1-nitro-2-phenoxy-benzene (1.3 g, 5.3 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (100 mL) was shaken under 50 psi of hydrogen for 20 hours. The mixture was filtered through Celite and evaporated, providing 1.1 g of the product as a light gold oil; 1H NMR (CDCl3) δ 3.70 (s, 3H), 6.49 (d, J=2.6 Hz, 1H), 6.59 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.96-7.00 (m, 2H), 7.07 (t, J=7.3 Hz, 1H), 7.28-7.35 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)([O-])=[O:2].O.O.O.C([O-])(=O)C.[Na+].N>O1CCCC1.CO>[OH:2][NH:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1
Reactant: O=C1CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1CN=C(c2ccccc2)c2cc(NO)ccc2N1
Reaction time: 0.33 h

Procedure:
A mixture of 16.8 g. of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one, 500 ml. of tetrahydrofuran, 250 ml. of methanol, 56 g. of stannous chloride dihydrate and 68 g. of sodium acetate trihydrate was stirred at room temperature under an atmosphere of nitrogen for 24 hours. 1 l. of tetrahydrofuran and 15 ml. of concentrated ammonia were then added. The inorganic salts were removed by filtration through celite. The filtrate was evaporated. The solid residue was stirred with 100 ml. of methylene chloride and 250 ml. of water for 20 minutes under nitrogen. The insoluble crystals were collected to leave light yellow material. For analysis it was recrystallized from ethanol/methylene chloride, m.p. 186°-187°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-])=O)=[CH:5][N:4]=1>CO.[Pd]>[CH3:1][NH:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([NH2:16])=[CH:5][N:4]=1
Reactant: CNc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CNc1cc(N2CCN(C)CC2)c(N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
N-methyl-4-(4-methylpiperazin-1-yl)-5-nitro-pyridin-2-amine (243 mg, 0.9670 mmol) was dissolved in methanol (10 mL) and Pd on C, wet, Degussa (50 mg, 0.4698 mmol) was added. The reaction was evacuated and filled with hydrogen three times and left to stir at RT overnight. The catalyst was filtered off and the solvent was removed under reduced pressure to yield N2-methyl-4-(4-methylpiperazin-1-yl)pyridine-2,5-diamine (173 mg, 81%). MS (ES+) 222.1.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][C:12](=[O:23])[C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]#[N:21])=[CH:15][C:14]=2[Cl:22])[CH:5]=[CH:4][N:3]=1.[CH3:24][C:25]1[N:30]=[C:29]([NH2:31])[CH:28]=[C:27]([CH3:32])[N:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC.O1CCOCC1>[Cl:22][C:14]1[CH:15]=[C:16]([C:20]#[N:21])[CH:17]=[C:18]([Cl:19])[C:13]=1[C:12]([NH:11][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:31][C:29]2[CH:28]=[C:27]([CH3:32])[N:26]=[C:25]([CH3:24])[N:30]=2)[C:7]=1[N+:8]([O-:10])=[O:9])=[O:23]
Reactant: Cc1cc(N)nc(C)n1
Reactant: N#Cc1cc(Cl)c(C(=O)Nc2ccnc(Cl)c2[N+](=O)[O-])c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: COCCOC
Product: Cc1cc(Nc2nccc(NC(=O)c3c(Cl)cc(C#N)cc3Cl)c2[N+](=O)[O-])nc(C)n1
Yield: 3.2 %

Procedure:
A 25 mL microwave tube containing N-(2-chloro-3-nitropyridin-4-yl)-2,6-dichloro-4-cyanobenzamide (100 mg, 0.27 mmol), 2,6-dimethylpyrimidin-4-amine (43 mg, 0.35 mmol), Pd2(dba)3 (8 mg, 0.009 mmol), Cs2CO3 (180 mg, 0.54 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 4 mg, 0.005 mmol), dioxane (8 mL) and DME (3 mL) was degassed and then charged by N2 (3×). The mixture was then irradiated in a microwave reactor at 160° C. for 2 hours and then diluted with dioxane (20 mL). The reaction was filtered through Celite and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (Gemini, 200 mm×25 mm, gradient: CH3CN/0.05% NH3.H2O, 50-80, 10 min) to afford the desired product (4 mg, yield: 5%). LCMS (ESI) m/z: 458.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=4)=[N:13][N:14]=[C:6]3[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]=2[N:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:27])[C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)=[N:13][N:14]=[C:6]3[N:5]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]=2[N:3]=1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCNC(=O)c3ccc(OC)cc3)nnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCNC(=O)c3ccc(O)cc3)nnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-[2-(7-bromo-5-oxo-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-3-yl)ethyl]-4-methoxybenzamide (63.0 mg, 0.125 mmol) in CH2Cl2 (5 mL) at 0° C. was added a solution of Boron tribromide in CH2Cl2 (1.0 M, 1.3 mL, 1.3 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and then concentrated and purified by preparative LCMS to give the desired product. LCMS calculated for C20H23BrN7O3 (M+H): m/z=488.1, 490.1. found: 488.0, 489.9.
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8](C(=O)C(F)(F)F)[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.CC(C)(C)CC(C1SC(C2C=CC(CN)=CC=2)=CC=1)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:10]1[C:4]2[CH:3]=[CH:2][CH:18]=[CH:17][C:5]=2[CH2:6][CH2:7][NH:8][CH2:9]1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)CC(=O)c1ccc(-c2ccc(CN)cc2)s1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCNCC2
Yield: 261.5 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (93.5 mg, 0.2 mmol) with 4-[5-(3,3-dimethylbutyryl)tiophen-2-yl]-benzylamine (129 mg, 0.4 mmol) using tris(dibenzylideneacetone)dipalladium(0) (40.3 mg, 0.04 mmol), BINAP (58.3 mg, 0.08 mmol) and cesium carbonate (100 mg, 0.3 mmol) in toluene/DMF (11:1, 12 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 7-chloro-6-{4-[5-(3,3-dimethylbutyryl)-tiophen-2-yl]-benzylamino}trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (77 mg, 62%). MS (ES+) m/z: 563 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[CH3:19])=[CH:4][N:3]=1.CCOC(C)=O>[Pd].CO>[NH2:16][C:14]1[CH:13]=[CH:12][C:11]([CH3:19])=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1)=[O:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)Nc1cnc(N)nc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1C(=O)Nc1cnc(N)nc1
Reaction time: 24 h

Procedure:
A round bottom flask equipped with a stir bar was charged with N-(2-aminopyrimidin-5-yl)-2-methyl-5-nitrobenzamide 8 (300 mg, 1.1 mmol), 10% Pd/C (˜150 mg), EtOAc (24 mL) and MeOH (6 mL). The mixture was purged with H2 (3× evacuation and back-fill cycles) then allowed to stir under an H2 balloon. After 24 h, TLC and LCMS indicated that the starting material was completely consumed. The mixture was filtered through a pad of Celite, washing with MeOH and CH2Cl2. Recrystalization from MeOH/CH2Cl2 afforded 5-amino-N-(2-aminopyrimidin-5-yl)-2-methylbenzamide 9 as a pale yellow crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H](C3C=CC=CC=3)C)[C:17](=[O:28])[CH2:16]2)[CH3:14])[C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:11]=[C:10]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:28])[CH2:16]2)[CH3:14])[C:5]2[N:6]([CH3:9])[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](c1ccccc1)N1C[C@H]([C@@H](C)Oc2cc(Br)cc3ncn(C)c23)CC1=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](Oc1cc(Br)cc2ncn(C)c12)[C@H]1CNC(=O)C1

Procedure:
(R)-4-((R)-1-(5-bromo-1-methyl-1H-benzo[d]imidazol-7-yloxy)ethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one 2.57 in TFA (2 mL) was heated in the microwave for 30 min at 140° C. The reaction mixture was then concentrated to give (R)-4-((R)-1-(5-bromo-1-methyl-1H-benzo[d]imidazol-7-yloxy)ethyl)pyrrolidin-2-one 2.58, which was used without further purification.
Reaction SMILES: O=[C:2]1[C:11]2[C:10]([C:12]([O:14]C)=O)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.[NH2:29][NH2:30]>>[C:22]1([CH:3]2[C:2]3=[N:29][NH:30][C:12](=[O:14])[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]=43)[NH:5][CH:4]2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccccn1)N2
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccn1)C2c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
A mixture of methyl 4-oxo-3-phenyl-2-(pyridin-2-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (30 mg, 0.08 mmol) and hydrazine monohydrate (1 mL) was stirred at room temperature for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered, 10 mg of 9-phenyl-8-(pyridin-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one was obtained, yield 37%. 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.60 (d, 1H), 4.86-4.88 (m, 1H), 5.21 (s, 1H), 6.96 (dd, 1H), 7.08-7.17 (m, 4H), 7.22-7.28 (m, 3H), 7.46-7.49 (m, 1H), 7.60 (t, 1H), 7.73 (dd, 1H), 8.59 (d, 1H), 9.77 (s, 1H); LC-MS (ESI) m/z: 341 (M+1)+.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:23])=[C:17]([CH2:20][CH2:21]Cl)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl.[NH:34]1[CH2:39][CH2:38][CH:37]([C:40]2[C:44]3[CH:45]=[CH:46][C:47]([OH:49])=[CH:48][C:43]=3[O:42][N:41]=2)[CH2:36][CH2:35]1>CO>[Si:1]([O:8][CH:9]1[C:14]2=[N:15][C:16]([CH3:23])=[C:17]([CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][CH:37]([C:40]4[C:44]5[CH:45]=[CH:46][C:47]([OH:49])=[CH:48][C:43]=5[O:42][N:41]=4)[CH2:38][CH2:39]3)[C:18](=[O:19])[N:13]2[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O[Si](C)(C)C(C)(C)C
Reactant: Oc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(O)ccc34)CC1)CCCC2O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A solution of 9-((tert-butyldimethylsilyl)oxy)-3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one, prepared as described in the previous step, (0.5 g, 1.40 mmol) in methanol (25 mL) and diisopropylethylamine (732.83 μL, 4.20 mmol) was treated with 3-(piperidin-4-yl)benzo[d]isoxazol-6-ol hydrochloride salt (374.62 mg, 1.47 mmol), and the reaction mixture was stirred for 17 h at 60° C. under argon. Diisopropylethylamine (732.83 μL, 4.20 mmol) was added and the mixture was stirred additionally for 4 h at 60° C. The reaction mixture was evaporated under vacuum and the residue was taken up in water (25 mL), extracted with chloroform (3×25 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent was removed under vacuum. The residue was purified by silica gel chromatography (elution with dichloromethane/methanol (98/2) to give the title compound (ESI-MS (M+1) 539).
Reaction SMILES: N1(C2C=CC(O[CH:11]3[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)=CC=2)C=CN=C1.CO.[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH:33]=O)=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:21][O:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([CH2:33][N:13]2[CH2:14][CH2:15][CH2:16][CH2:11][CH2:12]2)=[CH:25][CH:24]=1
Reactant: c1cn(-c2ccc(OC3CCCNC3)cc2)cn1
Reactant: COc1ccc(C=O)c2ccccc12
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2CCCCC2)c2ccccc12
Reaction time: 8 h
Yield: 16.8 %

Procedure:
To a mixture of 3-[4-(imidazol-1-yl)phenoxy]piperidine (308 mg, 1.26 mmol), methanol (6.0 mL) was added 4-methoxy-1-naphthaldehyde (1.25 eq, 298 mg), followed by borane pyridine complex (0.196 mL, 1.25 eq.). The resulting mixture was stirred overnight. The methanol was evaporated, and the residue diluted with ethyl acetate, washed with water and brine. Evaporation of the solvent in vacuo gave a crude product. Flash column chromatography on silical gel with 1-2% methanol in methylene chloride afforded 3-[4-(imidazol-1-yl)phenoxy]-]-1-[(4-methoxynaphth-1-yl)methyl]piperidine (54 mg), 1H NMR(CDCl3) 8.30 (m, 2), 7.70 (s, 1), 7.50 (m, 2), 7.30 (s, 1), 7.20 (m, 4), 6.90 (m, 2), 6.70 (d, 2), 4.30 (m, 1), 4.00 (s, 3), 3.90 (AB q , 2), 3.10 (m, 1), 2.80 (m, 1), 2.10-2.30 (m, 3), 1.80 (m, 1), 1.40-1.70 (m, 2) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH3:33])[CH:29]=4)[N:24]([CH3:34])[C:23]3=[O:35])[CH2:18][CH2:17]2)=[N:4][N:3]=1.O>C(O)(=O)C.[Pd]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[C:5]([N:16]1[CH2:17][CH2:18][CH:19]([N:22]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([CH3:33])[CH:29]=4)[N:24]([CH3:34])[C:23]3=[O:35])[CH2:20][CH2:21]1)=[N:4][N:3]=[CH:2]2
Reactant: COc1cc2c(Cl)nnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2cnnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Temperature: 40 °C
Reaction time: 3 h
Yield: 18.8 %

Procedure:
In 10 ml of acetic acid was dissolved 300 mg (0.61 mmol) of Compound 76 obtained in Example 58, and 40 mg of 10% palladium on carbon suspended in a small amount of water was added to the solution, followed by vigorous stirring at 40° C. for 3 hours under a hydrogen atmosphere at atmospheric pressure. The reaction mixture was filtered using a filter aid, and the filtrate was neutralized by addition of a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated aqueous solution of sodium chloride, and then dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=50/1). Ether was added to the product, and the precipitated crystals were collected by filtration, washed, and dried to give 52.9 mg (yield: 19%) of Compound 77 as white crystals.