Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:10]3([CH2:12][CH2:11]3)[CH2:9][O:8][C:7]=12.CN(C=O)C.Cl[C:20]1[N:25]=[CH:24][C:23]([N:26]2[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[NH:28][C:27]2=[O:34])=[CH:22][N:21]=1>>[CH3:32][C:29]1([CH3:33])[NH:28][C:27](=[O:34])[N:26]([C:23]2[CH:24]=[N:25][C:20]([O:13][C:5]3[C:6]4[C:10]5([CH2:9][O:8][C:7]=4[C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:12][CH2:11]5)=[N:21][CH:22]=2)[C:30]1=[O:31]
Reactant: Cc1ccc(O)c2c1OCC21CC1
Reactant: CC1(C)NC(=O)N(c2cnc(Cl)nc2)C1=O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncc(N3C(=O)NC(C)(C)C3=O)cn2)c2c1OCC21CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-ol (Intermediate 13, 18 mg, 0.1 mmol) in dry DMF (1 ml) potassium carbonate (27.6 mg, 0.2 mmol) and then 3-(2-chloropyrimidin-5-yl)-5,5-dimethyl-imidazolidine-2,4-dione (Intermediate 23, 20 mg, 0.083 mmol) were added and the reaction mixture was stirred for 2 hours at 80° C. After cooling the reaction mixture was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried over sodium sulfate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 7:3 to cyclohexane/ethyl acetate 3:7 as eluents affording the title compound (18 mg) as a light beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23](Br)[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[C:37](F)C=C[C:34]=1[N+:40]([O-])=O.[Si](C#C)(C)(C)C.C(N)CCC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[N:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[C:15](=[O:20])[N:14]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[C:23]([NH:40][CH2:34][CH2:33][CH2:38][CH3:37])[CH:22]=1)[CH:13]=[CH:12]2)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc([N+](=O)[O-])c(Br)c3)c(=O)c2cc1F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CCCCN
Solvent: CN(C)C=O
Product: CCCCNc1cc(-n2ccc3cc(N(C)C(=O)OC(C)(C)C)c(F)cc3c2=O)ccc1[N+](=O)[O-]

Procedure:
[2-(3-Bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester was generated by Method A (Example 46) using 2-bromo-4-fluoro-1-nitro-benzene. A mixture of [2-(3-Bromo-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (21 mg, 0.0427 mmol), tetrakis(triphenylphosphine)palladium(0) (2.5 mg, 0.002 mmol), copper (I) iodide (2 mg, 0.008 mmol), TMS acetylene (10 ul, 0.07 mmol), n-butylamine (1.5 ml) and 1 mL DMF was purged with argon for 2 minutes. The mixture was then subjected to microwave irradiation (120° C.) for 5 minutes, then diluted with ethyl acetate and washed with brine. The organic layers were combined and concentrated in vacuo to give a crude residue, which was purified by column chromatography (silica 5-25% EtOAc/hexane) to give [2-(3-butylamino-4-nitro-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][N:17]3[C@@H:26]([CH2:27][OH:28])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[C:11]([CH2:29][CH3:30])=[N:10]2)=[C:4]([CH3:31])[CH:3]=1.[H-].[Na+].[CH2:34](I)[CH3:35]>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]([CH2:14][CH3:15])=[C:12]([CH2:16][N:17]3[C@@H:26]([CH2:27][O:28][CH2:34][CH3:35])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[C:11]([CH2:29][CH3:30])=[N:10]2)=[C:4]([CH3:31])[CH:3]=1
Reactant: CCc1nn(-c2c(C)cc(Br)cc2C)c(CC)c1CN1Cc2ccccc2C[C@@H]1CO
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Reaction time: 0.08 h
Yield: 141.1 %

Procedure:
To an ambient temperature solution of (R)-{2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-1,2,3,4-tetrahydro-isoquinolin-3-yl }-methanol (0.45 g, 0.93 mmol) in anhydrous tetrahydrofuran (12 ml) was added sodium hydride (224 mg of 60% sodium hydride mineral oil dispersion; 5.6 mmol of sodium hydride was added. After stirring for 5 minutes, ethyl iodide (0.37 ml, 4.7 mmol) was added all at once. The reaction mixture was then stirred for 21 hours. The solvent was removed in vacuo, and the remaining residue was extracted with ethyl acetate/water (10 ml of each). The aqueous phase was separated, and then extracted twice with equal volumes of fresh ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo to afford a yellow oil (0.67 g). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl acetate/hexane =1:6 in volume) afforded the title compound as a light yellow oil (332 mg).
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[C:10]([I:11])=[C:9]([NH:12][C:13]([CH3:15])=[O:14])[C:8]([I:16])=[C:7]([C:17]([O-:19])=[O:18])[C:6]=1[I:20])=[O:3].[Na+].Cl[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C)C=O>[C:13]([NH:12][C:9]1[C:8]([I:16])=[C:7]([C:6]([I:20])=[C:5]([NH:4][C:2](=[O:3])[CH3:1])[C:10]=1[I:11])[C:17]([O:19][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:18])(=[O:14])[CH3:15]
Reactant: CCOC(=O)CCl
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COC(=O)c1c(I)c(NC(C)=O)c(I)c(NC(C)=O)c1I
Temperature: 25 °C
Yield: 75.7 %

Procedure:
To 175 mL of dry N,N-dimethylformamide (DMF) was added 63.6 g (0.100 mol) sodium diatrizoate and 14.7 g (0.120 mol) of ethyl chloroacetate and the mixture was heated on a steam bath for 6 hr. The reaction was filtered while hot and the filtrate cooled to room temperature and diluted to 500 ml with water. The mixture was cooled and filtered and the collected solid washed with water. The solid was then dissolved in 350 ml hot DMF, filtered and added to an equal volume of water. The mixture was cooled, filtered, washed with water, and the solid dried at 100° C. overnight to afford 53.0 g (76% yield) of a white powder, mp 269.5°-270.5° C. Analysis for C15H15I3N2O6 : Calculated/Found: C, 25.73/25.80; H, 2.15/2.77; I, 54.4/53.8.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][C:13]=2[CH3:22])[C:7]2[CH:23]=[CH:24][C:25]([C:27]#[N:28])=[CH:26][C:6]=2[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C@H:4]1[CH3:36].[C:37]([O:41][C:42]([N:44]([CH3:51])[C@@H:45]([CH2:49][CH3:50])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([C:25]1[CH:24]=[CH:23][C:7]2[N:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=[CH:14][C:13]=3[CH3:22])[C:9](=[O:10])[C@@H:3]([NH:2][C:46](=[O:47])[C@@H:45]([N:44]([CH3:51])[C:42](=[O:43])[O:41][C:37]([CH3:38])([CH3:39])[CH3:40])[CH2:49][CH3:50])[C@H:4]([CH3:36])[N:5]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:6]=2[CH:26]=1)#[N:28]
Reactant: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Cc1ccc2ccccc2c1CN1C(=O)[C@@H](N)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C)ccc3ccccc23)c2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a rt solution of (3S,4S)-3-amino-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (100 mg, 190 μmol) in DMF (632 μl) was added (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (45.3 mg, 209 μmol), N,N-diisopropylethylamine (131 μl, 759 μmol), and HBTU (79.2 mg, 209 μmol). The reaction was stirred at rt for 30 min, then purified by reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-4-methyl-1-((2-methylnaphthalen-1-yl)methyl)-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxobutan-2-yl(methyl)carbamate (118 mg, 90%) as a white solid. MS m/z 712 (MNa)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](OC)=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC>CN(C=O)C.[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:7]([O:6][P:4]([CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:22]=[CH2:23])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOP(=O)(COc1ccc(OC)cc1[N+](=O)[O-])OCC
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(OCP(=O)(OCC)OCC)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
A solution of 2-diethylphosphonomethyloxy-5-bromonitrobenzene (1 mmole, prepared as in Example 37, Step A) in DMF (5 mL) was treated with tributyl(vinyl)tin (1.2 mmole) and palladium bis(triphenylphosphine) dichloride (0.1 mmole), and the mixture was heated at 60° C. under nitrogen for 6 h. Evaporation and chromatography gave 2-diethylphosphonomethyloxy-5-vinylnitrobenzene as an oil which was subjected to Step B of Example 38, Step B of Example 36, and Step D of Example 34 to give 2-amino-7-ethyl-6-thiocyano-4-phosphonomethoxybenzothiazole (41.1). mp>167° C.(dec.). Anal. Calcd. for C11H12N3O4PS2: C, 38.26; H, 3.50; N, 12.17. Found: C, 37.87; H, 3.47; N, 11.93.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Br)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17](Cl)([Cl:20])(=[O:19])=[O:18]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:17]([Cl:20])(=[O:19])=[O:18])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Clc1cc(Br)cc(OCc2ccccc2)c1
Solvent: C1CCOC1
Product: O=S(=O)(Cl)c1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Under N2 atmosphere, 2.23 g 1-benzyloxy-3-bromo-5-chloro-benzene was dissolved in 50 mL dry THF, and the mixture was cooled in an ice bath. Dropwise, 14.84 mL of a 1M solution of isopropyl magnesium chloride—lithium chloride complex was added, and the mixture was stirred at room temperature overnight. After cooling to −40° C., 2.41 mL of sulfuryl chloride was added in one portion (T raised to 10° C.), and the mixture was stirred for 15 minutes at room temperature. After cooling with an ice bath, the mixture was quenched with water and acidified with 1M aqueous HCl. The mixture was extracted with MTBE, and the organic phase was dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (PA→PA/Et2O 95:5) to yield 1.53 g (62%) of a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.14 (s, 2H), 7.30 (t, J=2 Hz, 1H), 7.34-7.47 (m, 5H), 7.50 (t, J=2 Hz, 1H), 7.62 (t, J=1.5 Hz, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][C@@H:7]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[C:12]2[Br:22])[C@@H:6]1[O:23]C(=O)C)(=O)C.CO.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:22][C:12]1[N:11]([C@@H:7]2[CH2:8][CH2:9][CH2:10][C@@H:5]([OH:4])[C@H:6]2[OH:23])[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=1
Reactant: CC(=O)O[C@H]1[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)CCC[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O[C@@H]1[C@H](O)CCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reaction time: 3 h
Yield: 45 %

Procedure:
(±)-(1R*,2S*,3R*)-3-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclohexanediyl diacetate (part c of this example, 700 mg, 1.51 mmol) was dissolved in ethanol (12 ml)-methanol (12 ml)-water (3 ml). Sodium carbonate (160 mg, 1.5 mmol) was added and the mixture was stirred vigorously for 3 h. Volatiles were evaporated in vacuo and the residual solids were slurried in water. The solid was recrystallized from ethanol to give title compound as white powder (260 mg, 45%), m.p. 197-199° C. dec.; 1H-NMR (DMSO-d6, 200 MHz) δ: 8.26 and 7.92 (both s, each 1, 2 aromatic CH), 4.8-4.6 (m, 3, OCH and 2OH), 4.264.20 (m, 1, NCH), 4.17-3.98 (m, 1, OCH), 2.24-2.19 (m, 1, 1/2 CH2), 1.84-1.74 (m, 4, 2 CH2), 1.60-1.53 (m, 4, 1, 1/2 CH2).
Reaction SMILES: CO.C(=O)([O-])[O-].[K+].[K+].[C:9]([NH:12][C:13]([NH:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[CH3:25])=[S:14])(=O)[CH3:10].BrCC([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)=O>O>[CH3:25][C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[NH:15][C:13]1[S:14][CH:10]=[C:9]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[N:12]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: CC(=O)NC(=S)Nc1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(-c2cccnc2)cs1
Temperature: 27.5 °C

Procedure:
In a reactor, introduce methanol (1120 L), potassium carbonate (287 kg, 2076.70 mol) and 1-acetyl-3-(2-methyl-5-nitro-phenyl)-thiourea (67 kg, 264.53 mol). 2-bromo-1-pyridin-3-yl-ethanone (Int4) (52 kg, 259.96 mol) was then added and temperature maintained at 25-30° C. for 4 hours. Water (692 L) was added to the reaction mixture and precipitate filtered, washed with water and diisopropylether. The product was then dried in a tray drier at 45-50° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:11]([O:14][C:15](=[O:24])[CH:16]([NH2:23])[CH2:17][S:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:13])[CH3:12]>>[CH:11]([O:14][C:15](=[O:24])[CH:16]([NH:23][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][S:18][C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:13])[CH3:12]
Reactant: CC(C)OC(=O)C(N)CSC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CC(C)OC(=O)C(CSC(C)(C)C)NC(=O)c1ccccc1
Yield: 72.5 %

Procedure:
With General procedure D, starting from 21 (5.6 g, 40.4 mmol) and 16 (7.33 g, 28.65 mmol), 6.72 g (73%) of the title compound was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.54-7.43 (m, 3H), 6.97 (br d, 1H), 5.12 (m, 1H), 5.02 (m, 1H), 3.14 (dd, 2H), 1.30 (m, 15H). MS m/z 324 (M+1). HPLC: 96.61% (ACQ_PA95_C_BLS; Column: BEH_C18—2−1×50 mm—1-7 μm).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7].[CH3:28][O:29][CH2:30][CH2:31][CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:1][C:2]1[CH:26]=[CH:25][C:24]([O:27][CH2:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:23][C:3]=1[CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@H:9]1[CH2:21][CH3:22])=[O:7]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(O)ccc1F
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1cc(OCCCOC)ccc1F
Yield: 94 %

Procedure:
This compound was prepared from (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2-fluoro-5-hydroxy-benzyl) ester and toluene-4-sulfonic acid 3-methoxy-propyl ester according to the procedure described in Example 187 to give the product as a colorless oil (342 mg; 94%); MS (ISP): 472.4 (M+NH4)+.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:10]F>C(#N)C>[CH3:1][CH:2]([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)CC
Reactant: FF
Solvent: CC#N
Product: CCOC(=O)C(=O)C(C)F

Procedure:
In the same manner as in Example 1, ethyl 3-methylpyruvate (1.0 g; 8.62 mmol) is dissolved in acetonitrile (22.5 g) and reacted with fluorine. By distilling off the solvent under reduced pressure, there is obtained a crude product, which is rectified to give ethyl 3-methyl-3-fluoropyruvate.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][C:4]([N:7]=[C:8]=[N:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[CH:3][CH:2]=1.[CH2:28]([N:35]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][NH:41][CH3:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[CH:5][C:4]([N:7]2[CH:16]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:9]=[C:8]2[N:41]([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:42])=[CH:3][CH:2]=1
Reactant: COC(=O)C=Cc1ccccc1N=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CNCCCCCN(Cc1ccccc1)Cc1ccccc1
Product: COC(=O)CC1c2ccccc2N=C(N(C)CCCCCN(Cc2ccccc2)Cc2ccccc2)N1c1ccc(-c2ccccc2)cc1

Procedure:
Compound (11) is reacted with compound (18) in a suitable solvent to give 3-(4-biphenylyl)-2-[N-(5-dibenzylaminopentyl)-N-methylamino]-4-methoxycarbonylmethyl-3,4-dihydroquinazoline (19). Then, this compound (19) is hydrogenated in the presence of Pd(C) and formalin solution to give 2-[N-(5-N′,N′-dimethylaminopentyl)-N-methylamino]-3-(4-biphenylyl)-4-methoxycarbonylmethyl-3,4-dihydroquinazoline (20).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[I-:10].[K+].CN(C)C=O.Cl>[Cu](I)I.C(OCC)(=O)C>[I:10][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=Cc1ccc(Br)cc1
Agent: I[Cu]I
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccc(I)cc1
Reaction time: 1 h

Procedure:
8.0 g (43.2 mmol) of 4-bromobenzaldehyde, 107.6 g (0.65 mmol) of potassium iodide, 41.1 g (0.22 mmol) of copper iodide and 130 mL of dimethylformamide (DMF) were put in a 300 mL three-neck flask, and refluxed in a nitrogen atmosphere for 3 hours. After it was put back at a room temperature, 1N of hydrochloric acid and ethyl acetate were added, and stirred for 1 hour. It was filtered to remove potassium iodide and copper iodide, and the filtrate was washed with sodium sulfate and water, and dried with magnesium sulfate. It was distilled under a reduced pressure to obtain 4-iodobenzaldehyde (compound A). A synthesis scheme is shown below.
Reaction SMILES: [CH2:1]=[O:2].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1>C1COCC1>[N:3]1([CH2:1][OH:2])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C=O
Solvent: C1CCOC1
Product: OCn1cnc2ccccc21
Reaction time: 0.17 h

Procedure:
Formaldehyde (37% in water, 1 mL, 13.3 mmol) was added to a solution of 1H-benzo[d]imidazole (1.57 g, 13.3 mmol) in THF (60 ml). After 10 minutes, the solvent was removed and dried to give 1H-benzo[d]imidazol-1-ylmethanol as a brown solid which was used without any further purification. 1H NMR (DMSO-d6) δ 5.60 (d, J=7.09 Hz, 2H), 6.70 (m, 1H), 7.25 (m, 2H), 7.65 (d, J=9.13 Hz, 2H), 8.26 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]=[CH:6][C:7]1[C:15]2[C:10](=[CH:11][N:12]=[C:13]([N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)[CH:14]=2)[NH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].CO>[N:16]1([C:13]2[CH:14]=[C:15]3[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])=[CH:8][NH:9][C:10]3=[CH:11][N:12]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: CCOC(=O)C=Cc1c[nH]c2cnc(-n3cncn3)cc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1c[nH]c2cnc(-n3cncn3)cc12
Yield: 88.6 %

Procedure:
Ethyl-3-(5-(1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)prop-2-enoate (0.5 g, 1.8 mmol) was hydrogenated over palladium on carbon (10%, 0.2 g) in methanol (75 mL) at 45 psi of hydrogen for 90 min. The catalyst was removed by filtration and the solvent evaporated in vacuo to give the title compound (0.455 g, 90%) as a colourless solid. mp 129°-131° C. 1H NMR (360 MHz, CDCl3) δ 1.24 (3H, t, J=7.1Hz), 2.72 (2H, t, J=7.4Hz), 3.13 (2H, t, J=7.4Hz), 4.14 (2H, q, J=7.1Hz), 7.31 (1H, d, J=2.3Hz), 8.08 (1H, s), 8.11 (1H, s), 8.54-8.60 (2H, m) and 9.15 (1H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:21]1[CH:26]=[CH:25][C:24]([C:2]2[CH:3]=[C:4]([C:8]3[N:12]4[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: OB(O)c1ccncc1
Reactant: FC(F)(F)c1cnn2c(-c3cccc(Br)c3)cnc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: FC(F)(F)c1cnn2c(-c3cccc(-c4ccncc4)c3)cnc2n1
Temperature: 65 °C
Reaction time: 12 h
Yield: 44.9 %

Procedure:
A mixture of 7-(3-bromophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (21 mg, 0.06 mmol), 4-pyridylboronic acid (11 mg, 0.09 mmol) and 2 M Na2CO3 (0.09 ml) in 1,2-dimethoxyethane (1.5 ml) was degassed with a stream of nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) was added and the mixture was stirred under nitrogen at 65° C. for 12 h. After allowing to cool to room temperature, the mixture was diluted with ethyl acetate and partitioned between water (20 ml) and ethyl acetate (30 ml). The organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 5% MeOH/CH2Cl2) and triturated with diethyl ether to give 9.2 mg (44%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, m), 7.70 (1H, t, J 7.3 Hz), 7.74-7.77 (1H, m), 8.13 (1H, dt, J 7.3, 1.6 Hz), 8.39 (1H, t, J 1.6 Hz), 8.68 (1H, s), 8.72 (2H, m), 8.83 (1H, s); MS (ES+) m/z 342 [M+H]+.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3]/[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[O:21]=[O+][O-].CSC>ClCCl.N1C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][O:5][CH2:4]/[CH:3]=[C:2](/[CH3:1])\[CH2:15][CH2:16][CH:17]=[O:21])=[CH:12][CH:11]=1.[CH3:1]/[C:2](/[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3]/[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: O=[O+][O-]
Agent: COc1ccc(COC/C=C(/C)CCC=C(C)C)cc1
Solvent: CSC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COC/C=C(/C)CCC=O)cc1
Temperature: 25 °C

Procedure:
1-({[(2Z)-3,7-dimethylocta-2,6-dien-1-yl]oxy}methyl)-4-methoxybenzene (75.0 g, 273 mmol) was dissolved in dichloromethane (1.13 l) and pyridine (11.3 ml). This reaction solution was cooled to −78° C., to which ozone was bubbled (flow rate 2 l/min, electric voltage 90 V) for 170 minutes with stirring. After addition of dimethylsulfide (80.3 ml, 1.09 mol), the reaction solution was allowed to warm to room temperature and was stirred overnight. The reaction solution was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (Kanto Chemical, commercial name Silica gel 60N, granular, neutral, 0.040 mm-0.100 mm; n-heptane:ethyl acetate=4:1) and the title compound (36.9 g) was obtained as a colorless oil while 1-({[(2Z)-3,7-dimethylocta-2,6-dien-1-yl]oxy}methyl)-4-methoxybenzene (14.1 g) was recovered.