Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:31]=[N+:32]=[N-:33])(=[O:3])[CH3:2]>CC(O)=O>[C:1]([O:4][C@H:5]1[C@H:10]([OH:11])[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:31]=[N+:32]=[N-:33])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](N=[N+]=[N-])CCC[C@H]1OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1[C@H](O)CCC[C@@H]1N=[N+]=[N-]
Temperature: 56 °C
Yield: 81 %

Procedure:
Compound 3 (677 mg, 1.53 mmol) was dissolved in AcOH (10 mL), heated to 56° C. and left over night. The mixture was concentrated and purified by flash chromatography using EtOAc:n-heptan (1:1) as eluent. The reaction yielded 81% of 4. 1H-NMR (CDCl3) 4.72 (t, J=9.54 Hz, 1 H), 3.56 (m, 1 H), 3.47 (m, 1 H), 2.19 (s, 3 H), 2.00-2.10 (m, 3 H), 1.80 (m, 1 H), 1.25-1.45 (m, 3 H). HRMS calculated mass (C8H14N3O3+): 200.1030, observed mass: 200.1056.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].C(Cl)Cl>CS(C)=O.CCOCC.O>[N:17]1([C:10]2[CH:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:8]([CH:9]=2)[O:7][CH2:6][CH2:5][C:1]#[N:2])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1OCCBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCCOc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.6 %

Procedure:
Sodium cyanide (79 mg, 1.6 mmol) was added to 4-[3-(2-Bromo-ethoxy)-4-nitro-phenyl]-morpholine (447 mg, 1.35 mmol) in Dimethyl sulfoxide (5 mL) and the reaction was stirred at room temperature 48 h. The mixture was diluted with 50 mL Et2O and 20 mL water. DCM was added to solubilize ppt. The layers were separated and the aq. extracted 3×50 mL DCM. The combined organic extracts were washed with satd. sodium bicarbonate (50 mL) and brine (50 mL), conc. in vacuo and taken up in DCM for application to a 25 g SiO2 pre-load cartridge. Chromatography (0-100% EtOAc:Hex) afforded 3-(5-Morpholin-4-yl-2-nitro-phenoxy)-propionitrile as a yellow solid (212 mg, 57%). 1H-NMR (CDCl3): 8.01 (d, 1H, J=9.2 Hz), 6.52 (d, 1H, J=9.2 Hz), 6.40 (s, 1H), 4.31 (t, 2H, J=7.0 Hz), 3.86 (t, 4H, J=4.6 Hz), 3.35 (t, 4H, J=4.6 Hz), 2.93 (t, 2H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH3:2].[CH2:24]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][N:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]([N:6]([CH:20]1[CH2:22][CH2:21]1)[C:7](=[O:19])[C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:12][CH:13]=1)[C:36]([C:35]1[CH:34]=[N:33][C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:40][CH:39]=1)=[O:37])[CH3:2]
Reactant: O=C(O)c1ccc(OCc2ccccc2)nc1
Reactant: CCOC(=O)CN(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1
Product: CCOC(=O)C(C(=O)c1ccc(OCc2ccccc2)nc1)N(C(=O)c1ccc(OC(F)(F)F)cc1)C1CC1

Procedure:
The title compound, a colorless oil (1.5 g, 62%), was prepared in analogy to intermediate 8A by reaction of [cyclopropyl-(4-trifluoromethoxy-benzoyl)-amino]-acetic acid ethyl ester (intermediate 7B) with 6-(benzyloxy)nicotinic acid. MS: 543.2 (MH+).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]2[N:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=[O:23].O>C([O-])(O)=O.[Na+]>[C:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([NH:14][C:15](=[O:23])[CH3:17])=[C:12]([OH:16])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1nc2ccc(OC(=O)c3ccccc3)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(OC(=O)c2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methyl-1,3-benzoxazol-6-yl benzoate (5.05 g, 20 mmol) in THE (100 mL) a mixture trifluoroacetic acid/water (4 ml/10 mL) was added. The reaction mixture was stirred at room temperature for 16 h, then saurated aqueous NaHCO3 (150 mL) was added. The mixture was extracted with ethyl acetate (150 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the subtitled compound.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[C:7]([O:11][CH3:12])[CH:8]=2)[C:3]1=[O:15].P(OCC)(OCC)OCC.[CH2:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH:39]=O)[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([N-]C(C)C)(C)C.[Li+]>[Pd].O1CCCC1>[CH3:12][O:11][C:7]1[CH:8]=[C:9]2[CH2:10][CH:2]([CH2:39][CH:36]3[CH2:35][CH2:34][N:33]([CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:38][CH2:37]3)[C:3](=[O:15])[C:4]2=[CH:5][C:6]=1[O:13][CH3:14]
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc2c(cc1OC)C(=O)C(Br)C2
Agent: [Pd]
Agent: CC(C)[N-]C(C)C
Agent: CCOP(OCC)OCC
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Yield: 50.8 %

Procedure:
There are many processes as disclosed in the prior arts for producing donepezil of formula 1. U.S. Pat. No. 4,895,841 wherein substituted 1-indanone-2-phosphonate prepared from 2-bromo-5,6-dimethoxyindanone and triethyl phosphite, is treated with 1-benzylpiperidine-4-carboxaldehyde in the presence of a strong base, such as lithium diisopropylamide (LDA), followed by catalytic reduction using palladium on carbon in tetrahydrofuran (40 volumes) to yield donepezil with an overall yield of 50.8%. This process however suffers with few limitations i.e. it employs triphenylphosphonium methoxymethyl chloride, which is expensive and toxic and the overall yield of this process is quite low. (scheme 1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=O.[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19]>CC(C)=O>[N:19]1[C:3]([C:5]2[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=2)=[CH:2][N:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=12
Reactant: O=Cc1ccc(C(=O)CBr)cc1
Reactant: Nc1ncccn1
Solvent: CC(C)=O
Product: O=Cc1ccc(-c2cn3cccnc3n2)cc1
Reaction time: 8 h

Procedure:
4-(bromoacetyl)benzaldehyde is dissolved in acetone. To it is added pyrimidin-2-amine (1 eq). The reaction mixture is stirred overnight. The precipitated solid is filtered off and dried to obtain the desired compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]([F:66])([F:65])[CH2:54][O:55][C:56]1[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][N:57]=1>C1COCC1.CCOC(C)=O>[F:66][C:53]([F:52])([F:65])[CH2:54][O:55][C:56]1[CH:64]=[CH:63][C:59]([C:60]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]3[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]3)=[CH:4][CH:3]=2)=[O:61])=[CH:58][N:57]=1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(N)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(NC(=O)c3ccc(OCC(F)(F)F)nc3)cc2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.3 %

Procedure:
To a stirred suspension of (S)-tert-butyl 2-(4-aminophenyl)morpholine-4-carboxylate (1.5 g) in THF (75 ml) were added sequentially N-methylmorpholine (1.78 ml), HBTU (3.07 g) and 6-(2,2,2-trifluoroethoxy)nicotinic acid (1.63 g) and the mixture was stirred at room temperature for 17 h. The suspension was diluted with EtOAc and washed sequentially with 0.5 M aq. HCl, sat. aq. NaHCO3 and saturated brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by recrystallisation from heptane/EtOAc (1:1) to give (S)-tert-butyl 2-(4-(6-(2,2,2-trifluoroethoxy)nicotinamido)phenyl)morpholine-4-carboxylate (2.11 g, 81%) as a white solid. MS (ISP): 482.1 ([M+H]+).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(=O)([O-])[O-].[K+].[K+].[Br:13][C:14]1[CH:15]=[C:16]([C:26]2[O:27][C:28](=[O:38])[C:29]3[N:35]=[C:34]([Cl:36])[CH:33]=[C:32]([CH3:37])[C:30]=3[N:31]=2)[N:17]([C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1.O>C1COCC1.O.C(OCC)(=O)C>[Cl:36][C:34]1[N:35]=[C:29]([C:28]([N:4]([CH3:3])[NH:5][CH3:6])=[O:38])[C:30]([NH:31][C:26]([C:16]2[N:17]([C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=3)[N:18]=[C:14]([Br:13])[CH:15]=2)=[O:27])=[C:32]([CH3:37])[CH:33]=1
Reactant: CNNC
Reactant: Cc1cc(Cl)nc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CNN(C)C(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.3 %

Procedure:
1,2-Dimethylhydrazine dihydrochloride (176 mg) and potassium carbonate (366 mg) were suspended in THF (8 mL) and 10 drops of water, 2-[5-bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-6-chloro-8-methyl-pyrido[3,2-d][1,3]oxazin-4-one (example 7, step 4) (300 mg) was added and the reaction mixture was stirred for 20 h at room temperature. Water and ethyl acetate were added, the layers were separated and the aqueous layer was 2× extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate=1:1, Rf=0.13) to afford 300 mg of the title compound of the formula
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[N:6]=[C:5]2[C:11]([F:14])([F:13])[F:12]
Reactant: C1=COCCC1
Reactant: FC(F)(F)c1n[nH]c2ccc(Br)cc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: FC(F)(F)c1nn(C2CCCCO2)c2ccc(Br)cc12
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)-1H-indazole (500 mg, 1.887 mmol) in DCM (10 mL) was added 3,4-dihydro-2h-pyran (0.517 mL, 5.66 mmol) and p-toluenesulfonic acid monohydrate (35.9 mg, 0.189 mmol). The solution was stirred for 1 h. The solution was diluted with DCM, washed with saturated NaHCO3 and concentrated. The residue was purified by flash chromatography on silica gel with eluting with 10% EtOAc/Hexane to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-indazole as a colorless oil (610 mg, 93%). 1NMR: 400 MHz, CDCl3: δ ppm 1.69-1.75 (m, 7H), 2.12-2.17 (m, 2H), 2.48-2.51 (m, 1H), 3.61 (d, J=85.20 Hz, 3H), 3.72-3.78 (m, 2H), 3.87-3.99 (m, 3H), 4.56 (s, 1H), 5.77 (dd, J=4.00, 8.00 Hz, 1H), 7.52-7.60 (m, 2H), 7.96 (t, J=24.40 Hz, 1H).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([N:14]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:3][CH:2]=1.C1C(=O)N([Br:34])C(=O)C1.O>CN(C=O)C>[Br:34][C:23]1[CH:24]=[CH:25][C:26]2[N:14]([C:4]3[C:5]4[S:6][C:7]5[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=5[C:9]=4[CH:1]=[CH:2][CH:3]=3)[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)sc1c(-n3c4ccccc4c4ccccc43)cccc12
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1cccc2c1sc1ccccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9-(dibenzo[b,d]thiophen-4-yl)-9H-carbazole (6 g, 17.17 mmol) was dissolved in 100 mL of DMF. The solution was cooled to 0° C. To the solution was added NBS (3.36 g, 18.89 mmol) in 20 mL of DMF dropwise. After stirring at this temperature for 1 h, HPLC indicated there was very little reaction. The reaction was warmed to room temperature and monitored by HPLC. After 24 h, 500 mL of water was added to the reaction and stirred at room temperature for 2 h. The white precipitate was filtered and washed with water. The solid was dissolved in DCM and washed with water and dried over MgSO4. The residue was used directly for the next step. The product contains 10% of starting material, 80% of desired product and 10% of dibrominated product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=2)[NH:28][N:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:35][C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[NH:28][N:27]=[C:26]4[Cl:25])=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[Cl:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH2:35])[CH:33]=2)[NH:28][N:27]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Agent: Nc1ccc2[nH]nc(Cl)c2c1
Product: CCC(C(=O)Nc1ccc2[nH]nc(Cl)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
In two batches, a total of 242 mg (0.68 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 404 mg (purity 31%, 0.75 mmol, 1.1 eq.) of 3-chloro-1H-indazole-5-amine were reacted according to General Method 1. The combined crude products were purified by repeated preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 18 mg (purity 94%, 13% of theory) of the title compound Example 196 and 65 mg (55% of theory) of the title compound Example 197, which was isolated as a by-product due to the starting material 3-chloro-1H-indazole-5-amine employed being contaminated with 1H-indazole-5-amine.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=C[C:39]=2N=N1.C(N(CC)CC)C>C(OCC)C.CO>[NH:1]([C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[C@@H:2]([C:11]([O:13][CH3:39])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)[C@@H](Cc1ccc(C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.2 %

Procedure:
Fmoc—p—Me—D—Phe—OH (5 g) was dissolved in dichloromethane/methanol 9/1 v/v (50 ml). 2-(1H-benzotriazol-1-yl 1,1,3,3-tetramethyluronium tetrafluoroborate (4.4 g) was added and the solution adjusted to pH 8 by addition of triethylamine. The reaction mixture was stirred for 16 hours at room temperature. The mixture was washed successively with cold 1N hydrochloric acid solution, water, 5% sodium hydrogencarbonate, and water and dried over sodium sulphate. The filtrate was evaporated yielding 5.6 g of Fmoc—p—Me—D—Phe—OMe as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([F:11])=[C:6]([F:12])[CH:5]=1)=O.[N:13]1[NH:14][C:15](=[O:19])[CH:16]=CC=1>>[F:12][C:6]1[CH:5]=[C:4]([C:2]2[CH:1]=[CH:16][C:15](=[O:19])[NH:14][N:13]=2)[CH:9]=[C:8]([F:10])[C:7]=1[F:11]
Reactant: CC(=O)c1cc(F)c(F)c(F)c1
Reactant: O=c1cccn[nH]1
Product: O=c1ccc(-c2cc(F)c(F)c(F)c2)n[nH]1

Procedure:
20 g of 3,4,5-trifluoroacetophenone are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]2)=[CH:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCNc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCNc1ccc(OC2CCN(C)CC2)cc1
Yield: 79.5 %

Procedure:
To a solution of the compound of Example 68 (1.5 g) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (0.15 g) and the mixture was heated under reflux for hours. Water was added to the mixture and the precipitate formed was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (developing solvent: methylene chloride/methanol=10/1 (v/v)) to obtain 4-(4-hexylaminophenyloxy)-1-methylpiperidine (0.92 g) as a brown oil. The oil was dissolved in ethanol (20 ml), conc. hydrochloric acid (0.53 ml) was added to the solution and the solvent was distilled off to leave a solid. The solid was recrystallized from ethanol/ethyl ether to obtain 4-(4-hexylaminophenyloxy)-1-methylpiperidine dihydrochloride (0.76 g) as white crystals, m.p. 163°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1Br.Br[C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:9][C:6]1[CH:5]=[C:4]([C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21])[CH:3]=[C:2]([Cl:1])[C:7]=1[C:22]([F:25])([F:24])[F:23]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC1(C)OB(c2cc(Cl)c(Br)c(Cl)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 113.2 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(bromo)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 2.86 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.60 g, 3.43 mmol), Cs2CO3 (2.86 mL, 2M, 5.72 mmol) and Pd(PPh3)2Cl2 (60 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene (0.6 g; yield 66.7%) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.72 (s, 2 H), 6.38 (s, 1 H), 6.28 (s, 1 H) ppm.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC(C)(C)c1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, white solid (61 mg, 68%), MS (ISP) m/z=358.5 [(M+H)+], mp 215° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-tert-butyl-phenylboronic acid (57.9 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([C:21]2[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[CH3:29])([CH3:20])[C:18]#[N:19])[C:11]=1[CH3:30]>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]([C:21]2[C:22]([CH3:29])=[CH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])([CH3:20])[C:18]#[N:19])[C:11]=1[CH3:30])[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(C(C)(C#N)c2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc(C(C)(C#N)c2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 145.8 %

Procedure:
To a solution of 3-pentanol (140 mg, 1.59 mmol) in 2 ml of dry THF was added sodium hydride (60% in oil, 38 mg) and the mixture was stirred at room temperature for 5 minutes. 2-(6-Chloro-2,5-dimethylpyrimidin-4-yl)-2-(2,4,6-trimethylphenyl)-propionitrile (100 mg, 0.319 mmol) was added to the reaction mixture, and the resulting mixture was heated at reflux for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a brown oil (170 mg). The residue was purified through chromatotron using 20% ethyl acetate in hexane as eluent to give a mixture of two isomers as a yellow glass form and both having a M+ of 365 from GC/Ms. 1H NMR (CDCl3) δ 6.8 and 6.76 (s, 2H), 4.08 and 3.96 (m, 1H), 3.25 and 3.22 (s, 3H), 2.36 and 2.30 (s, 3H), 2.21, 2.20 and 2.06 (s, total of 9H), 1.5–1.7 (m, 4H), 1.04 (s, 3H), 0.96 and 0.90 (t, 3H) ppm.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4C(=O)CCCC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:35][C:36]1([C:40]2[CH:45]=[CH:44][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52](=[O:62])[N:51](C)[CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([C:40]2[CH:41]=[CH:42][C:43]([C:46]3[C:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)=[CH:54][C:53]4[C:52](=[O:62])[NH:51][CH2:50][CH2:49][C:48]=4[N:47]=3)=[CH:44][CH:45]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: CN1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)NCC4)cc2)CCC1
Yield: 144.4 %

Procedure:
Following the procedure for 2-(4-(1-aminocyclobutyl)phenyl)-3-phenyl-7,8-dihydroquinolin-5(6H)-one, tert-butyl(1-(4-(6-methyl-5-oxo-3-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)phenyl)cyclobutyl)carbamate (29 mg, 0.06 mmol) was reacted to afford the title compound (32 mg, 87%). LCMS (Method A): RT=3.76 min, M-NH2=367. 1H NMR (500 MHz, MeOD): 8.29 (1H, S), 7.49 (2H, d), 7.42 (2H, d), 7.30-7.29 (3H, m), 7.21-7.19 (m, 2H), 3.80 (2H, t), 3.30 (2H, t), 3.20 (3H, s), 2.78-2.72 (m, 2H), 2.60-2.54 (m, 2H), 2.27-2.18 (m, 1H), 2.00-1.91 (m, 1H).
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:16]12[O:23][CH2:22][C:19]([CH3:24])([CH2:20][O:21]1)[CH2:18][O:17]2)[CH2:12][CH:13]([CH3:15])[CH3:14])C1C=CC=CC=1>CCO.[Pd]>[CH3:14][CH:13]([CH3:15])[CH2:12][CH:11]([NH2:10])[C:16]12[O:17][CH2:18][C:19]([CH3:24])([CH2:20][O:21]1)[CH2:22][O:23]2
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2
Agent: [Pd]
Solvent: CCO
Product: CC(C)CC(N)C12OCC(C)(CO1)CO2
Reaction time: 6 h

Procedure:
To [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-carbamic acid benzyl ester (3.2 g, 9.2 mmol) in absolute EtOH (30 mL) was added 10% Pd in activated carbon (320 mg, 10%) under nitrogen. The reaction mixture was hydrogenated at 50 psi for 6 h. The reaction was monitored by TLC and the reaction mixture was filtered through Celite. The solvent was removed to get 3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butylamine as a white solid.