Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[CH3:18][N:19](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.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>[C:18]([C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1)#[N:19]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCc1cccc(C#N)c1
Temperature: 150 °C
Yield: 64.3 %

Procedure:
tert-Butyl [2-(3-bromophenyl)ethyl]carbamate (0.60 g, 1.99 mmol) was dissolved in dry DMF (18 mL) in a under nitrogen atmosphere. Zinc cyanide (0.47 g, 3.99 mmol) and tetrakis(triphenylphosphine)palladium (0.18 g, 0.16 mmol) was added. The reaction mixture was heated in a microwave reactor at 150° C. for 20 mins. The procedure was repeated two more times with equal amount of starting material and the resulting three mixtures were combined and diluted with EtOAc. The mixture was washed with saturated aqueous NaHCO3 and water, dried with Na2SO4, filtered and evaporated. The crude product was purified using Biotage Horizon HPFC system using Heptane and EtOAc as eluant affording the title compound (0.95 g, 64.3%). 1H NMR (500 MHz, CDCl3): δ 1.39 (s, 9H), 2.82 (t, 2H), 3.34 (q, 2H), 4.75 (bs, 1H), 7.37-7.50 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 28.57, 36.09, 41.63, 79.61, 112.69, 119.05, 129.56, 130.38, 132.57, 133.68, 140.86, 156.06.
Reaction SMILES: BrC1C=C(C#C)C=CC=1F.[NH2:11][C:12]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:21][CH:20]=2)[N:13]=1>CO>[NH2:11][C:12]1[N:16]([CH3:17])[C:15](=[O:18])[C@:14]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([Br:36])[CH:30]=2)([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([F:28])[F:27])=[CH:23][CH:24]=2)[N:13]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2ccc(F)c(Br)c2)N=C1N
Agent: C#Cc1ccc(F)c(Br)c1
Solvent: CO
Product: CN1C(=O)[C@@](c2ccc(OC(F)F)cc2)(c2ccc(F)c(Br)c2)N=C1N

Procedure:
Using essentially the same procedure described in Example 1, steps a-c, and employing 3-bromo-4-fluoro-1-ethynylbenzene the racemic mixture of 2-amino-5-(3-bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one was obtained and separated by chiral chromatography technique (Chiralcel OJ, 0.46×10 cm, using 15% ethanol in 85% hexane and diethylamine as the mobile phase) to give the title enantiomer, MS m/e (M+H)+ 332; 1H NMR (400 MHz, DMSO-d6) 2.94 (s, 3H), 6.74 (brs, 2H), 7.1 (d, J=8.75 Hz, 2H), 7.13-7.65 (m, 5H), 7.67 (d, J=2.2 Hz, 1H); [a]25=−22 (C=1% in MeOH).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4](C(C)(C)C=C)[C:5]([O:7][CH3:8])=[O:6].COC(=O)C(CC=C(C)C)C(OC)=O>>[C:5]([O:7][CH3:8])(=[O:6])[CH2:4][C:3]([O:2][CH3:1])=[O:14]
Reactant: C=CC(C)(C)C(C(=O)OC)C(=O)OC
Agent: COC(=O)C(CC=C(C)C)C(=O)OC
Product: COC(=O)CC(=O)OC

Procedure:
A mixture of bis(dibenzalacetone)palladium (0) (0.23 g, 0.4 mmole) and triphenylphosphine (0.84 g, 3.2 mmoles) in tetrahydrofuran (10 ml) is stirred at room temperature under argon for a few minutes to generate the catalytically active species. To the catalyst solution is added 2-methyl-3-buten-2-yl acetate (51.27 g, 400 moles) prepared according to Example 1 and a tetrahydrofuran solution of preformed dimethyl sodiomalonate prepared from sodium hydride (10.77 g) and dimethyl malonate (59.45 g, 450 mmoles). The resulting solution is maintained at reflux overnight under argon. The solvent (tetrahydrofuran) is removed by distillation and the residue after quenching with water is extracted with ether. After drying the ether is evaporated to leave 90 g of residue. Distillation at reduced pressure gives 69.0 g (86.1 percent) of colorless liquid (boiling point 110° C., 3.5 mm) shown by gas-liquid chromatography, infrared and nuclear magnetic resonance to be a 3:1 mixture of dimethyl(1,1-dimethylallyl)malonate and dimethyl(3,3-dimethylallyl)malonate.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>>[CH3:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Cl
Reactant: C1CNCCN1
Product: Cc1cccnc1N1CCNCC1

Procedure:
Reaction of the 2-chloro-3-methylpyridine with piperazine in a sealed bomb further using the procedure of Example 1 above resulted in a 50% yield of the desired IIIc product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[C:8]([OH:10])=O.[CH3:12][NH:13][C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([O:29]CCC)=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3>>[CH3:12][N:13]([C:8](=[O:10])[CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:11])[C@H:14]1[CH2:33][N:18]2[C:19]3[C:24]([C:25]([CH2:26][C:27]([OH:29])=[O:28])=[C:17]2[CH2:16][CH2:15]1)=[CH:23][CH:22]=[CH:21][CH:20]=3
Reactant: CC(C(=O)O)c1ccccn1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CC(C(=O)N(C)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1)c1ccccn1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 2-(pyridin-2-yl)propanoic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 392.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[C:7]([O:23][CH3:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.S(Cl)([Cl:27])=O.[OH-].[Na+]>CN(C=O)C>[ClH:27].[Cl:1][CH2:3][C:4]1[CH:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:11]2[C:6](=[C:7]([O:23][CH3:24])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc2c(NCc3ccccc3C)cc(CO)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cccc2c(NCc3ccccc3C)cc(CCl)nc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2 5 g (=7.2 mmol) of 2-hydroxymethyl-8-methoxy-4-(2-methylbenzylamino)quinoline hydrochloride, 5.3 ml of thionyl chloride and 2 drops of DMF was stirred at room temperature for 90 minutes. The mixture was poured onto ice, made alkaline with 1 N NaOH and extracted with ethyl acetate. The crude product after the organic phase had been dried with Na2SO4 and the solvent had been stripped off was converted into the hydrochloride with methanolic hydrochloric acid. 2.48 g of 2-chloromethyl-8-methoxy-4-(2-methylbenzylamino)quinoline hydrochloride were obtained.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.I[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].[ClH:26]>O1CCCC1.[Cl-].[Zn+2].[Cl-].[Pd].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.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.O>[ClH:26].[C:1]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COc1ccc(I)c(CCN(C)C)c1
Reactant: C#CCCCC
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC#Cc1ccc(OC)cc1CCN(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
A solution of 2.7 ml (0.027 mole) 1-hexyne in 10 ml dry (4 A sieves) tetrahydrofuran was cooled to 0° C. in an ice bath. Argon was passed over the solution 10.4 ml (0.027 mole) 2.69 M n-BuLi was added slowly via syringe through a serum cap. The resulting solution was stirred 20 minutes under argon. During this time, a second flask containing 3.2 g (0.027 mole) anhydrous zinc chloride was attached to the first flask via cannula. After the 20 minutes the contents of the first flask was transferred to the second flask via cannula. The second flask was cooled to 0° C. This solution was stirred for 20 minutes, then 5 g (0.016 mole) 2-iodo-5-methoxy-N,N-dimethylbenzeneethanamine in 20 ml dry tetrahydrofuran was added via syringe. 0.32 g (mole 1%) tetrakis(triphenylphosphine) palladium was added to the reaction mixture which was stirred overnight at room temperature under nitrogen. Water was added to the reaction mixture and the organics were evaporated in vacuo. The residue was taken up in methanol, the solid catalyst was filtered off and the methanol was evaporated in vacuo. Methylene chloride was added to the aqueous residue, the organic layer was washed with sodium bicarbonate solution, water, brine solution and dried over potassium carbonate. The organics were evaporated in vacuo to give a red oil. Addition of ethereal hydrogen chloride gave white crystals which upon recrystallization from acetonitrile gave 1.27 g (27% yield) of 2-(1-hexynyl)-5-methoxy-N,N-dimethylbenzeneethanamine hydrochloride, mp 145.5°-147.5° C.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH2:13]([N:15]=[C:16]=[S:17])[CH3:14]>>[C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:16]([NH:15][CH2:13][CH3:14])=[S:17])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NNc1ccc(N)cc1
Reactant: CCN=C=S
Product: CCNC(=S)Nc1ccc(NNC(C)=O)cc1

Procedure:
1-Acetyl-2-(4-aminophenyl)hydrazine (1.65 g, 0.01 mole) and ethyl isothiocyanate (0.87 g, 0.01 mole) were reacted according to procedure (11.). Yield 1.7 g (67%), m.p. 191°-193° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[C:8](=[CH:18]\[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)/[C:9]([NH:11][C:12]2[S:13][C:14]([Cl:17])=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.CCOCC>[Cl:17][C:14]1[S:13][C:12]([NH:11][C:9](=[O:10])/[C:8](/[C:5]2[CH:6]=[N:7][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][CH:4]=2)=[CH:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[N:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CS(=O)(=O)Nc1ccc(/C(=C\C2CCCC2)C(=O)Nc2ncc(Cl)s2)cn1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of (E)-2-(6-aminopyridin-3-yl)-N-(5-chlorothiazol-2-yl)-3-cyclopentylacrylamide (EXAMPLE 75, 50 mg, 143 μmol) in anhydrous CH2Cl2 (3 mL) was treated with pyridine (570 μL, 7.1 mmol) and MsCl (170 μL, 2.2 mmol). After stirring for 3 d at 20° C., the reaction mixture was diluted with Et2O (40 mL), before being extracted with 1M NaOH-saturated aqueous NaHCO3 (1:1, 2×15 mL). The combined aqueous extracts were neutralised with 2M HCl, before being extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (1:1 IH-EtOAc) furnished the title compound: RTA=3.73 min; m/z (ES+)=427.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][N+:11]([O-])=O)[C:4]=1[O:14][CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:15][O:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:9][CH2:10][NH2:11]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1cccc(CCN)c1OC

Procedure:
In close analogy to the procedure described above, 1,2-Dimethoxy-3-(2-nitro-vinyl)-benzene is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: C(=[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]1[CH2:11][NH2:12])C(C)C.[CH3:13][C:14]([O-])([CH3:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:5][C:6]=1[CH:11]=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C=C1C=CC=NC1CN
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN=Cc1ccccn1
Yield: 1583.3 %

Procedure:
The procedure is carried out as described in Example 1 (b) but with the use of 138 g (0.85 mol) of isobutylidene-2-aminomethylpyridine, 150 ml of toluene and 4 g (0.036 mol) of potassium tert-butylate. After a reaction time of 30 minutes at 40° C. and subsequent distillation, there is obtained 92 g (0.57 mol) of 2-pyridylmethylidene-isobutylamine; yield 67% of theory; b.p. 95° C./2.0×103Pa.
Reaction SMILES: C([O:3][C:4]([CH:6](C(OCC)=O)[C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([F:16])=[CH:9][N:8]=1)=O)C.C(OCC)(=O)CC(OCC)=O.NC1C(C(C(OCC)=O)C(OCC)=O)=NC=C(F)C=1>C(O)C.[Ni].O.Cl>[F:16][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][C:4](=[O:3])[NH:13]2)=[N:8][CH:9]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: CCOC(=O)C(C(=O)OCC)c1ncc(F)cc1N
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C1Cc2ncc(F)cc2N1

Procedure:
The mixture of 2-bis(ethoxycarbonyl)methyl-5-fluoro-3-nitropyridine and diethyl malonate was dissolved in ethanol (100 mL) and added to a suspension of 50% Raney nickel in water (7.8 g) diluted with ethanol (150 mL). The mixture was hydrogenated in a Parr shaker at 3 atmospheres pressure overnight and then filtered through diatomaceous earth (Celite (trademark)) to remove the catalyst. The solvent was removed in vacuo to leave a mixture of 3-amino-2-bis(ethoxycarbonyl)methyl-5-fluoropyridine and diethyl malonate as an oil. The mixture containing 3-amino-2-bis(ethoxycarbonyl)methyl-5-fluropyridine and diethyl malonate was taken up in 6N HCl solution (280 mL) and heated at reflux for 3 hours. After removing the aqueous acid in vacuo, the residue was taken up in water and again concentrated to leave a solid. This was taken up in dry ethanol and concentrated two times to obtain the title compound as a light green solid (4.07 g) which was triturated with hot ethyl acetate and dried in the air. Although somewhat impure by NMR this material was used in directly in the next step without further purification.
Reaction SMILES: C[N:2](C)/[C:3](/[CH3:14])=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=O.[NH:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][N:25]=1)[C:21]#[N:22])N.CC(O)=O>CCO>[CH3:14][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[N:16]([C:18]2[CH:19]=[C:20]([C:21]#[N:22])[CH:23]=[CH:24][N:25]=2)[N:2]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: C/C(=C\C(=O)c1ccc(C)cc1)N(C)C
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(-c2cc(C)nn2-c2cc(C#N)ccn2)cc1
Yield: 56.3 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-(4-methylphenyl)but-2-en-1-one (227 mg, 1.1 mmol) and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol, PREPARATION 2) in 10 mL EtOH was added 2 mL AcOH. The reaction mixture was heated under reflux conditions overnight before being cooled and concentrated to dryness. The residue was adjusted to pH>8 with saturated aq. K2CO3 and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 20 mL brine, dried, and concentrated to dryness to give the title compound (170 mg, 55.6%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 2.38 (6H, s), 6.30 (1H, s), 7.15 (4H, s), 7.33 (1H, d, J=4.0 Hz), 7.78 (1H, s), 8.44 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4, 275; Found, 275.
Reaction SMILES: BrC1C=C([C@@H]2[C@@H](C3C=C(F)C=CC=3F)[O:11][C:10](=O)N2)C=NC=1.Cl.Cl.[NH2:24][C@H:25]([C:35]1[CH:40]=[C:39]([Cl:41])[N:38]=[CH:37][N:36]=1)[C@@H:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1)[OH:27]>>[Cl:41][C:39]1[N:38]=[CH:37][N:36]=[C:35]([C@@H:25]2[C@@H:26]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[O:27][C:10](=[O:11])[NH:24]2)[CH:40]=1
Reactant: N[C@H](c1cc(Cl)ncn1)[C@H](O)c1cccc(F)c1
Reactant: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Agent: Cl
Product: O=C1N[C@H](c2cc(Cl)ncn2)[C@@H](c2cccc(F)c2)O1

Procedure:
Prepared according to the same procedure as (4R,5R)-4-(5-bromopyridin-3-yl)-5-(2,5-difluorophenyl)oxazolidin-2-one, starting with (1R,2R)-2-amino-2-(6-chloropyrimidin-4-yl)-1-(3-fluorophenyl)ethanol 2HCl. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.55 (s, 1H), 7.86 (s, 1H), 7.52 (td, J=7.9, 6.1 Hz, 1H), 7.42-7.17 (m, 3H), 5.62 (d, J=4.9 Hz, 1H), 4.93 (d, J=5.2 Hz, 1H), Mass spec.: 294.1 (MH)+.
Reaction SMILES: C([NH:4][CH:5]([C:13]1[NH:14][C:15]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:16]=2[N:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=O)C.ClCCl.C(O)C>Cl.CO>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([CH:5]([NH2:4])[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[NH:14][C:15]=2[CH:21]=1
Reactant: CC(=O)NC(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: NC(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1

Procedure:
1.35 g (4.302 mmol) of rac.-N-acetyl-1-(5-chlorobenzimidazol-2-yl)-2-phenylethylamine is placed in a mixture of 20 mL of 4 molar hydrochloric acid and 15 mL of methanol and the mixture is refluxed for 2 hours. Then all the volatile constituents are removed under reduced pressure. The crude product is further reacted directly. Rf value: 0.50 (silica gel; dichloromethane/ethanol=8:2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])O.[Na+].[CH:16](B1OC(C)(C)C(C)(C)O1)=[CH2:17]>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.O.O1CCOCC1>[CH:16]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])=[CH2:17]
Reactant: CC(=O)c1ccccc1Br
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: C1COCCO1
Solvent: O
Product: C=Cc1ccccc1C(C)=O
Temperature: 95 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
A solution of 2′-bromoacetophenone (1.6 mL, 12 mmol), sodium hydrogencarbonate (2.5 g, 30 mmol), vinylboronic acid pinacol ester (3.0 mL, 18 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.69 g, 0.60 mmol) in a mixed solvent (50 mL), which consists of water and 1,4-dioxane (1:4), was stirred at 95° C. for 2.5 hours. Water (100 mL) was added to the reaction solution and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate. After the organic layer was filtered with celite and the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography to give the title reference compound (1.2 g) as an orange oil (Yield 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCOc1ccc(-c2ccc(F)cc2)cc1
Yield: 88.8 %

Procedure:
Using 2.8 g (14.9 mmol) of 4-fluoro-4'-hydroxybiphenyl, 50 ml of acetonitrile, 2.17 g (15.6 mmol) of 3-bromopropanol and 4.11 g (30 mmol) of anhydrous potassium carbonate, synthetic treatment was carried out in the same manner as in Example 2. The obtained colorless powder was recrystallized from benzene/n-hexane to obtain 3.26 g (yield: 89%) of 4-fluoro-4'-(3-hydroxypropoxy)biphenyl (18) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19]1([CH3:24])OCC[O:20]1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:19](=[O:20])[CH3:24])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]2=[O:25]
Reactant: CCOC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C(C)=O

Procedure:
Ethyl 2-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (220 mg, 34%) in the same manner as described in the above example 6 (20) from ethyl 3-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.75 g, 2.13 mmol) and p-toluenesulfonic acid monohydrate (100 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])[CH3:4].C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>C(Cl)Cl>[CH3:18][C:2]([CH3:17])([CH3:1])[C@@H:3]([N:5]([CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])[C:26](=[O:27])[O:28][CH3:29])[CH3:4]
Reactant: COC(=O)Cl
Reactant: C[C@H](NCCC(=O)c1ccc(F)cc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)N(CCC(=O)c1ccc(F)cc1)[C@@H](C)C(C)(C)C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of (S)-3-(3,3-dimethylbutan-2-ylamino)-1-(4-fluorophenyl)propan-1-one (2.00 g, 7.97 mmol) and K2CO3 (3.30 g, 23.9 mmol) in CH2Cl2 (100 mL) was added methyl chloroformate (2.25 g, 23.9 mmol) dropwise at 0° C., and the reaction mixture was stirred at it overnight. The solution was filtered, and the filtrate was concentrated to give the crude product, which was purified by chromatography to afford (S)-methyl 3,3-dimethylbutan-2-yl(3-(4-fluorophenyl)-3-oxopropyl)carbamate (2.0 g, 81%). 1H NMR (CDCl3): 0.92 (s, 9H), 1.12-1.21 (d, 3H), 3.02-3.11 (m, 1H), 3.27-3.49 (m, 1H), 3.66 (s, 3H), 3.98-4.23 (m, 1H), 7.06-7.17 (m, 2H), 7.92-8.08 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32].C(OCC)(=[O:35])C>C(O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH2:21])=[O:35])[CH:15]=2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32]
Reactant: CCOC(C)=O
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccnc(C#N)c3)c(=O)c1Br)C2(C)C
Solvent: CCO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccnc(C(N)=O)c3)c(=O)c1Br)C2(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(2-cyanopyridin-4-yl)methyl]acetamide (34.0 mg, 0.07 mmol) was dissolved in ethanol/30% aqueous potassium hydroxide (4 mL, 1:1) and stirred at 80° C. for 2 hours. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=8/1) to give the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]2[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=2[CH:52]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:38]=[CH:39][C:40]3[O:45][CH2:44][C:43](=[O:46])[N:42]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]=3[CH:52]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1CCOCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCOCCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.500 g of tert-butyl 3-hydroxy-4-(4-{2-[2-(2-methoxyphenyl)ethoxy]ethoxy}phenyl)piperidine-1-carboxylate and 0.314 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2b) are reacted. The title compound is obtained as an opaque oil. Rf=0.24 (1:1 EtOAc-heptane); Rt=5.82.