Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8](Br)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[Mg].Cl[C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.O>C1COCC1.BrCCBr>[CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]
Reactant: Clc1ccc2ccccc2n1
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Solvent: BrCCBr
Product: CCCN(CCC)C1CCc2cccc(-c3ccc4ccccc4n3)c2C1
Reaction time: 1.5 h
Yield: 181.9 %

Procedure:
2-Di-n-propylamino-8-bromo-1,2,3,4-tetrahydronaphthalene (1 g, 3.22 mmol) was added to a refluxing mixture of magnesium turnings (120 mg, 4.9 mmol) in 50 ml THF. Formation of the Grignard reagent was initiated by addition of 0.2 ml 1,2-dibromoethane (0.002 mmol). After 1.5 hours, 220 mg (0.33 mmol) Ni[PPh3 ]2Cl2 in 10 ml of THF were added followed by 800 mg (4.89 mmol) of 2-chloroquinoline. The solution continued to reflux for 15 minutes after which it was cooled, poured into water, and extracted three times with methalene chloride. The extract was dried with sodium sulfate and concentrated to obtain 2.1 g of a black oil. The crude was purified by using two flash columns. The first was eluted with 1:1 hexanes:ether and the second with 20:1 methylene chloride:methanol. 130 mg of the title compound were collected as product. Following crystallization in ethanol and water, 66 mg of solid were recovered, m.p. 82° C. Analysis: Theory (.1/3 H2O): C, 82.37; H, 8.48; N, 7.68; Found: C, 82.33; H, 8.44; N, 7.73.
Reaction SMILES: Br[C:2]1[S:6][N:5]=[C:4]([CH3:7])[CH:3]=1.C([Mg]Cl)(C)C.[Cl:13][C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1>C1COCC1.[Cl-].[Zn+2].[Cl-].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[Cl:13][C:14]1[N:15]=[N:16][C:17]([C:2]2[S:6][N:5]=[C:4]([CH3:7])[CH:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1cc(Br)sn1
Reactant: Clc1ccc(Cl)nn1
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(Cl)nn2)sn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-bromo-3-methylisothiazole (2.42 g, 14 mmol) in 20 mL of THF at −45° C. was added isopropylmagnesium chloride (19 ml, 19 mmol) in THF (1 M). After 20 minutes, zinc(II) chloride (41 ml, 20 mmol) in THF (0.5 M) was added and the solution was warmed up to rt. 3,6-dichloropyridazine (2.4 g, 16 mmol), 3,6-dichloropyridazine (2.4 g, 16 mmol) and Q-Phos (2.5 g) were added and the reaction was heated to 50° C. for 16 hours. The reaction was then cooled to 23° C. and quenched with 60 mL of satd. NH4Cl aq. solution. The mixture was mixed with celite and 100 mL of EtOAc. The insoluble material was removed by filtration. The filtrate was diluted with 40 mL of EtOAc and 30 mL of water. The organic phase was separated and washed with 60 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (10% to 80% hex/EtOAc) to afford red solid as desired product. MS (ESI pos. ion) m/z: 212 (MH+). Calc'd exact mass for C8H6ClN3S: 211.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].S(=O)(=O)(O)O.[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([C:23](O)=[O:24])[C:17]=1[Cl:26]>O>[NH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[N:19]=[C:18]([C:23]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])=[O:24])[C:17]=1[Cl:26]
Reactant: Nc1cc(Cl)nc(C(=O)O)c1Cl
Reactant: CCCCC(CC)CO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCC(CC)COC(=O)c1nc(Cl)cc(N)c1Cl

Procedure:
To a solution of 2-ethylhexanol (10 mL) and sulfuric acid (1 mL) was added 4-amino-3,6-dichloro-pyridine-2-carboxylic acid (0.0097 mol, 2.0 g). After heating the reaction to reflux overnight, the reaction mixture was cooled, poured into water (75 mL), and extracted with ethyl acetate (75 mL). The organic phase was washed with sodium bicarbonate (75 mL), dried (Na2SO4), and concentrated. The resulting solid was recrystallized out of dichloromethane and hexane and filtered to give 2-ethylhexyl 4-amino-3,6-dichloropyridine-2-carboxylate (0.0074 mol, 2.36 g) as a crystalline solid (mp 55° C.). 1H NMR (CDCl3): δ 0.9 (7 H, m), 1.3 (7 H, m), 1.7 (1 H, m), 4.3 (2 H, d), 5.1 (2 H, bs), 6.7 (1 H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH2:23](Br)[C:24]#[CH:25].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.ClCCl.CN(C)C=O>[CH2:25]([N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1)[C:24]#[CH:23]
Reactant: C#CCBr
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C#CCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (30 mg, 0.1 mmol) produced in Example (8b), propargyl bromide (14.3 mg, 0.12 mmol), potassium carbonate (20.8 mg, 0.15 mmol) and dimethylformamide (1 mL) was stirred for 4 hours and 20 minutes at an external temperature of 80° C. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate-dichloromethane. The separated organic layer was washed with water, and then the solvent was distilled off by nitrogen stream. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 1-prop-2-ynyl-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1.Cl.CO>C(Cl)(Cl)Cl.CCOCC>[ClH:20].[F:1][C:2]1[CH:18]=[CH:17][C:16]2[NH+:15]([CH3:19])[C:14]3[C:6]([N:7]=[C:8]4[C:13]=3[CH:12]=[CH:11][CH:10]=[CH:9]4)=[C:5]([Cl:20])[C:4]=2[CH:3]=1
Reactant: Cn1c2c3ccccc3nc-2c(Cl)c2cc(F)ccc21
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C[NH+]1C2=c3ccccc3=NC2=C(Cl)c2cc(F)ccc21
Yield: 178.5 %

Procedure:
A solution of 2-fluoro-5-methylquindoline from Example 24 (100 mg) in chloroform (50 mL) was treated at room temperature with a 1 M solution of HCl in ether until a yellow solution/precipitate formed. Methanol was added to homogenize the mixture and then the solution was concentrated. The resulting solid was recrystallized from hot CHCl3 (50 mL)/EtOH (5 mL), with a minimum amount of ether being added to facilitate the crystallization process. Filtration, followed by washing the product with diethyl ether and drying afforded 101 mg (90.2%) of the title compound as yellow crystals, mp 211.8-212.5° C.; 1H NMR (DMSO-d6) δ 13.55 (s, 1H), 8.99 (dd, J=10.0, J=4.4, 1H) 8.82 (d, J=8.4, 1H), 8.40 (dd, J=9.2, J=2.8, 1H), 8.25-8.18 (m, 1H), 7.99 (dt, J=8.4, J=0.8, 1H), 7.88 (d, J=8.0, 1H), 7.56 (dt, J=8.4, J=0.8, 1H), 5.04 (s, 3H); 13C NMR (DMSO-d6) δ 160.48 (d, J=250.5), 146.01, 138.95, 134.75, 132.85, 132.53, 127.58 (d, J=5.6), 126.71, 124.94 (d, J=10.6), 122.51 (d, J=9.3), 122.33 (d, J=27.5), 122.20, 114.42, 113.56, 108.44 (d, J=25.4), 40.02; MS (EI, m/z) 285 (M+), 287 (M+2+)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[F:31][C:32]([F:39])([F:38])[C:33]1[CH:34]=[N:35][NH:36][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([N:35]3[CH:34]=[C:33]([C:32]([F:39])([F:38])[F:31])[CH:37]=[N:36]3)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(-n3cc(C(F)(F)F)cn3)c21
Temperature: 200 °C

Procedure:
Under argon atmosphere, 200 mg (purity 62%, 0.24 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2.5 ml of absolute acetonitrile, and 656 mg (4.82 mmol) of 4-(trifluoromethyl)-1H-pyrazole, 157 mg (0.48 mmol) of caesium carbonate, 7 mg (0.05 mmol) of copper(I) oxide and 26 mg (0.19 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→100:0). 85 mg (63% of theor.) of the target compound was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[C:8]#[CH:9].[Br:11][C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[OH:20].[F-].[Cs+].CN(C)C1C=CC=CC=1.Cl>CN(C=O)C.C(OCC)(=O)C>[Br:11][C:12]1[C:13]2[O:20][C:8]([CH3:9])=[CH:7][C:14]=2[C:15]([F:19])=[C:16]([F:18])[CH:17]=1
Reactant: C#CCBr
Reactant: Oc1cc(F)c(F)cc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(F)c(F)cc(Br)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
Potassium carbonate (1.38 g, 10.0 mmol) and propargyl bromide (0.414 mL, 5.50 mmol) were added to a solution (25 mL) of 2-bromo-4,5-difluorophenol (1.05 g, 5.00 mmol) in DMF, and stirred at room temperature overnight. The solvent was distilled away under reduced pressure, and after diluted with ethyl acetate, the resultant was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled away, and the residue was purified by silica gel chromatography (hexane/ethyl acetate). To the resulting compound (1.18 g, 4.78 mmol), cesium fluoride (872 mg, 5.74 mmol) and dimethylaniline (7 mL) were added, and stirred at 170° C. overnight. To the reaction solution, ethyl acetate and a 2 N hydrochloric acid aqueous solution were added and stirred. After the insoluble material was filtered off, extraction was performed with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane) to thus obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C([O:12][C:13]([C:15]1[C:16]([OH:30])=[N:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=2)=O)C.C(Cl)Cl>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:13]([C:15]1[C:16]([OH:30])=[N:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:27])[F:28])[CH:19]=2)=[O:12]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1O
Solvent: CCO
Solvent: ClCCl
Product: O=C(NCc1cccc(F)c1)c1c(O)nc2cc(C(F)(F)F)ccc2c1O
Temperature: 90 °C
Yield: 97.7 %

Procedure:
2.0 ml (17.3 mmol) 3-fluorobenzylamine was added to a suspension of 1.3 g (4.3 mmol) 2,4-dihydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in EtOH (50 ml) and the mixture was heated to 90° C. for 3 h. Concentration in a vacuum was subsequently carried out. After CC (DCM) of the residue, 1.6 g (4.2 mmol, 98%) N-(3-fluorobenzyl)-2,4-dihydroxy-7-(trifluoromethyl)quinoline-3-carboxylic acid amide was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10]2.[CH2:24]([NH:26][CH2:27][CH2:28][OH:29])[CH3:25]>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:12]2[C:13]3[C:9](=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:24][CH3:25])[CH2:27][CH2:28][OH:29])=[C:15]([F:16])[CH:14]=3)[CH:10]=[CH:11]2)=[CH:18][CH:19]=1
Reactant: CCNCCO
Reactant: Fc1ccc(-n2ccc3cc(OCCCCBr)c(F)cc32)cc1
Product: CCN(CCO)CCCCOc1cc2ccn(-c3ccc(F)cc3)c2cc1F

Procedure:
In analogy to example 23.7, 5-(4-Bromo-butoxy)-1-(4-fluoro-phenyl)-6-fluoro-1H-indole and 2-(ethylamino)ethanol were converted to yield 2-({4-[1-(4-Fluoro-phenyl)-6-fluoro -1H-indol-5-yloxy]-butyl}-ethyl-amino)-ethanol as light yellow oil, MS: 389 (MH+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[C:28]1([S:34]([OH:37])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([O-:37])(=[O:36])=[O:35]
Reactant: O=S(=O)(O)c1ccccc1
Agent: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: O=S(=O)([O-])c1ccccc1
Temperature: 42.5 °C
Reaction time: 3 h

Procedure:
Quetiapine free base (5.0 g) was dissolved in acetone (50 ml) at room temperature. This was followed by the addition of benzene sulfonic acid (2.0 g) at 30 to 35° C. The resulting mass was heated at 40-45° C. and maintained for 30 minutes. The resulting mass was cooled at 25-30° C. This was followed by the addition of diethyl ether (50 ml) and stirred for 3 hours. The precipitated product was collected by filtration under nitrogen and washed with diethyl ether (25 ml) and dried under vacuum to give the title compound as off white powder (5.94 g).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14]([C:21]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=O)[CH2:13][CH2:12]2.O.[OH-].[Na+]>O1CCCC1>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[CH2:15][N:14]([CH2:21][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:13][CH2:12]2
Reactant: COc1cc2c(cc1OC)CN(C(=O)C1CCNCC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)CN(CC1CCNCC1)CC2

Procedure:
A 1 M solution of LiAlH4 in dry tetrahydrofuran (12 ml) was added dropwise to a solution of (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)(piperidin-4-yl)methanone (2 g, 6.6 mmol) in dry tetrahydrofuran (60 ml) under argon atmosphere. The mixture was refluxed overnight. Water was added to the crude, made alkaline with 1 N NaOH and the salts formed was filtered over celite. Extraction with ethyl acetate yielded a solution that was dried with Na2SO4 and concentrated in vacuo to give and oil that was purified by flash chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH2:7][C:8](=[O:22])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:10](=O)[CH2:11][C:5]=2[CH:4]=1.[Cl-].[NH4+].O.ClCCl>C1COCC1>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[CH2:7][C:8](=[O:22])[N:9]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CN2C(=O)Cc3cc(OC)c(OC)cc3CC2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C=Cc3cc(OC)c(OC)cc3CC2=O)cc1
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1 g of LiBH(Et)3 (1.12 mmol, 1.33 eq, 1M solution in THF) is added to a solution of 7,8-dimethoxy-3-(4-methoxybenzyl)-1H-3-benzazepine-2,4(3H,5H)-dione (300 mg, 0.84 mmol) in THF (4.5 mL) at −78° C. The reaction mixture is held at that temperature for 1 hour 30 minutes with stirring and then hydrolysed with saturated aqueous ammonium chloride solution (4 mL). After a slow return to ambient temperature, 2 mL of water and 5 mL of dichloromethane are introduced, the aqueous phase is extracted with 10 mL of dichloromethane, and the organic phase is dried. The crude product obtained is purified by flash chromatography on a silica column (dichloromethane/methanol 98/2) to obtain the title product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14](I)=[CH:13][C:10]=3[C:11]=2[N:12]=1.[CH2:20]([N:23]([CH3:25])[CH3:24])[C:21]#[CH:22].O>C(N(CC)CC)C.CN(C=O)C.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.[Cu](I)I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:19])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([C:22]#[C:21][CH2:20][N:23]([CH3:25])[CH3:24])=[CH:13][C:10]=3[C:11]=2[N:12]=1
Reactant: C#CCN(C)C
Reactant: Nc1ncc2c(n1)-c1cc(I)c(Cl)cc1NC(=O)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Temperature: 75 °C
Reaction time: 8 h
Yield: 109.8 %

Procedure:
A solution of 2-amino-9-chloro-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.66 g, 4.29 mmol) and propargyl(dimethylamine) (0.74 mL, 6.89 mmol) in triethylamine (7 mL) and DMF (7 mL) was degassed with argon. To this solution was added bis(triphenylphosphine)palladium(II) chloride (0.30 g, 0.43 mmol) and copper iodide (0.163 g, 0.86 mmol). The reaction mixture was allowed to stir at 75° C. overnight. After the reaction mixture was allowed to cool to rt, water was added. The precipitate that formed was filtered and dried to give 2-amino-9-chloro-10-[3-(dimethylamino)prop-1-yn-1-yl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (1.61 g, 98%) as a brown solid. LCMS (FA): m/z=342 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)[NH:10][CH:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=2)[CH3:12])[C:21]2[CH:22]=[C:23]([NH2:27])[CH:24]=[CH:25][CH:26]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc(N)c2)cc1
Yield: 91.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[1-(3,5-difluorophenyl)ethyl]amine (2.65 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (3.16 g) and sodium borohydride (1.0 g) were reacted, to afford the title compound (2.24 g) as a pale orange oil.
Reaction SMILES: I[C:2]1[C:3]([CH3:17])=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[C:6]=1[CH3:7].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:3]([CH3:17])=[N:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=3)[C:6]=2[CH3:7])=[CH:22][CH:21]=1
Reactant: Cc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c(C)nn(-c3ccc(CCO)cc3)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(4-iodo-3,5-dimethyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2 of Example 11) and 4-methoxyphenylboronic acid: MS (ESI) m/z 323 [M+H]+H-NMR (CDCl3) δ 7.39 (2H, d, J=8.1 Hz), 7.29-7.22 (4H, m), 6.98 (2H, d, J=9.6 Hz), 3.86 (3H, s), 3.74 (2H, br), 2.86 (2H, t, J=6.6 Hz), 2.33 (3H, s), 2.28 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([NH2:31])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[C:39](Cl)([O:41][CH2:42][CH:43]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49]2[C:44]1=[CH:45][CH:46]=[CH:47][CH:48]=2)=[O:40]>O1CCOCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([NH:31][C:39]([O:41][CH2:42][CH:43]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:49]=2[C:50]2[C:55]1=[CH:54][CH:53]=[CH:52][CH:51]=2)=[O:40])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCOc1ccc(-c2ccc(CC[C@@H](N)CC(=O)OC(C)(C)C)cc2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@H](CC(=O)OC(C)(C)C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc2)cc1
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a stirred suspension of (R)-3-amino-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.14 g) in 50% aqueous 1,4-dioxane (40 ml) were added Na2CO3 (1.19 g, 11.2 mmol) and FmocCl (1.28 g, 4.95 mmol). After being stirred for 1 h, the mixture was diluted with sat. brine (100 ml) and extracted with CH2Cl2 (100 ml×3). The combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give (R)-3-(9-fluorenylmethoxycarbonylamino)-5-(4′-heptyloxybiphenyl-4-yl)pentanoic acid tert-butyl ester (crude, 3.34 g) which was used for the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH:19]([O:21]CCCC)=[CH2:20]>C(Cl)(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]([C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH:8]([CH3:10])[CH3:9])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CC(C)n1cc(Br)ccc1=O
Reactant: C=COCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1ccc(=O)n(C(C)C)c1
Temperature: 92.5 °C
Reaction time: 8 h

Procedure:
5-Bromo-1-isopropyl-2(1H)-pyridone (50 g) was dissolved in n-butyl vinyl ether (250 ml). To the solution were added 1,3-bis(diphenylphosphino)propane (6.3 g) and powdered K2CO3 (38.2 g) and Pd(OAc)2 (1.56 g) at 25° C. The mixture was heated at 90-95° C. with stirring for 8 hours. The reaction mixture was cooled to 25-30° C. To the cooled mixture was added CHCl3 (125 ml). The precipitated salt was removed by filtration and washed with CHCl3 (125 ml). Evaporation of solvent in the filtrate in vacuo gave oily residue. The residue was dissolved in CHCl3 (125 ml). To the solution was added 1N HCl (125 ml). The reaction mixture was stirred at 25-30° C. for 1 hour. The organic layer was separated. The aqueous layer was extracted with CHCl3 (100 ml). The combined organic layer was washed with 10% aq. NaHCO3 (50 ml) and dried over MgSO4 (25 g) and silica gel (25 g). MgSO4 and silica gel were removed by filtration and washed with CHCl3. Evaporation of solvent in the filtrate in vacuo gave oily residue, which was crystallized from n-hexane (500 ml). The crystal was collected by filtration and dried in vacuo at 40° C., to give 5-acetyl-1-isopropyl-2(1H)-pyridone (32.35 g).