Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[Cl-].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Zn+])=[CH:15][CH:14]=1>O1CCCC1.O.C(OCC)(=O)C.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.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]>[Br:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: N#Cc1ncc(Br)cc1Br
Agent: [Pd]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ncc(Cc2ccc(F)cc2)cc1Br
Temperature: 85 °C
Yield: 57 %

Procedure:
3,5-dibromo-2-pyridinecarbonitrile (4.52g, 15.34 mmol) was dissolved in tetrahydrofuran (75 mL) and palladium tetrakis(triphenylphosphine) (0.887g, 0.767 mmol) and 4-fluorobenyl zinc chloride (46.02 mL, 0.5 M in tetrahydrofuran) were added. The mixture was heated at 85° C. for 1 hour. An additional 12.3 mL of 4-fluorobenyl zinc chloride was added and the reaction was heated 40 minutes and allowed to cool to ambient temperature. The mixture was diluted with water and ethyl acetate and several drops of 1 N hydrochloric acid were added and the reaction was extracted with ethyl acetate. The organics were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel chromatography (0-100% ethyl acetate/hexanes gradient elution) gave 3-bromo-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (2.54g, 57% yield) as a pale yellow solid. 1H NMR (CDCl3) δ 8.48 (s, 1 H), 7.74 (s, 1 H), 7.15-7.11 (m, 2 H), 7.07-7.02 (m, 2 H), 4.02 (s, 2 H); MS m/z 292 (M+1).
Reaction SMILES: C[O:2][P:3]([CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]([CH2:27][CH3:28])=[C:14]2[CH2:29][C:30]([NH2:32])=[O:31])(=[O:6])[O:4]C.C[Si](Br)(C)C.CO>C(Cl)Cl>[NH2:32][C:30](=[O:31])[CH2:29][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][P:3](=[O:2])([OH:6])[OH:4])[CH:12]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]=1[CH2:27][CH3:28]
Reactant: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(OC)OC)ccc2n1Cc1ccccc1
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1c(CC(N)=O)c2cc(OCCCP(=O)(O)O)ccc2n1Cc1ccccc1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
[3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester (150 mg, 0.33 mmol) and 0.35 mL (2.6 mmol) of trimethylsilyl bromide in 2 mL of methylene chloride was stirred for 16 hours, 5 mL of MeOH added, stirred 1.0 hour and concentrated at reduced pressure. The residue was crystallized from EtOAc/MeCN/HOAc/water to give 138 mg (97% yield) of [3-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid, mp, 194°-196° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34].[CH3:37]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][S:16][C:17]3[N:18]([CH3:37])[CH:19]=[C:20]([CH2:24][C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[N:27][CH:26]=4)[C:21](=[O:23])[N:22]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:33]([F:35])([F:36])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Solvent: CI
Solvent: ClCCl
Product: COc1ncc(Cc2cn(C)c(SCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.5 %

Procedure:
To a solution of 2-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]thio}-5-{[2-(methyloxy)-5-pyrimidinyl]methyl}-4(1H)-pyrimidinone (300 mg, 0.561 mmol) and DIPEA (0.294 mL, 1.682 mmol) in DCM (15 mL) was added MeI (0.053 ml, 0.841 mmol). The mixture was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (100 mg, 32.5% yield). LCMS: rt=3.49 min, [M+H+]=549
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](Br)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.C(O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=2)=[CH:11][C:10]=1[C:24]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=[N:26][N:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCn1nnnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: Cc1ccccc1
Solvent: CCO
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(F)(F)F)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 71.2 %

Procedure:
The mixture of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-1-(3-methoxy-propyl)-1H-tetrazole (110 mg, 0.22 mmol) and 3-trifluoromethylphenylboronic acid (83 mg, 0.44 mmol) was heated in a mixture of toluene (2 ml), ethanol (2 ml) and saturated sodium bicarbonate (2 ml) under nitrogen in the presence of a catalytic amount of Pd(PPh3)4 (20 mg) at 80° C. for 2-3 h. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (15 ml×3), and the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to provide 5-(4,6-bis-benzyloxy-3′-trifluoromethyl-biphenyl-3-yl)-1-(3-methoxy-propyl)-1H-tetrazole (90 mg, 72%). 400 MHz 1H NMR (CDCl3) δ: 7.84 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.58-7.48 (m, 3H), 7.39-7.22 (m, 10H), 6.77 (s, 1H), 5.11 (s, 2H), 5.10 (s, 2H), 4.33 (t, J=7.6 Hz, 2H), 3.25 (t, J=6.0 Hz, 2H), 3.16 (s, 3H), 2.10-2.09 (m, 2H); LCMS: 575 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.CON(C)[C:21](=[O:28])[CH2:22][CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.OS([O-])(=O)=O.[K+]>C1COCC1>[CH:23]1([CH2:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:4][CH:3]=2)=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: CON(C)C(=O)CC1CCCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: O=C(CC1CCCC1)c1ccc(C2OCCO2)cc1
Temperature: -75 °C

Procedure:
2-(4-Bromophenyl)dioxolane from Example C (7 g, 0.03 mole) was dissolved in 75 mls of THF and cooled to -75° C. under argon. Tert.butyl lithium (29 ml of 1.7M solution in hexane) was added slowly at -76° C. maintaining the temperature such that it never rose above -40° C. After addition was complete, the solution was recooled to -78° C. and 4.2 g, 0.024 moles) of the product of Example B was added in THF. After completion of the addition, the solution was allowed to warm to 0° C., poured into 0.5N KHSO4 and extracted with ethyl acetate. After washing with brine, the extract was dried over Na2SO4. After the solvent was removed, the residue was chromatographed on silica with 10% ethyl acetate/hexane to give 2.8 g of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15](O)=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:32])=O>ClCCl>[CH2:1]([CH:3]([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([Cl:32])=[O:16])=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:18][C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)O)ccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To 8.00 g of 1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid in 100 ml of dichloromethane 0.1 ml of DMF and 4 ml of oxalyl chloride were added. The reaction was stirred at rt for 16 h, then concentrated and co-distilled with toluene to obtain 8.47 g (100%) of the crude product as a brown solid, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[NH:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28]3)=[CH:23][C:22]=2[CH:34]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([CH2:26][CH:27]3[CH2:28][N:29]([CH3:33])[CH2:30][CH2:31][N:32]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:15])=[CH:23][C:22]=2[CH:34]=1
Reactant: CN1CCNC(Cc2cc3cc(Cl)ccc3o2)C1
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCN(C)CC2Cc2cc3cc(Cl)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (135 mg) was prepared from 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (211 mg) and 3-(5-Chloro-benzofuran-2-ylmethyl)-1-methyl-piperazine, D63 (200 mg) by a procedure similar to that described for Example 1.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:20]([O:22]C)=[O:21])=[CH:9][NH:10][C:11]=2[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:8]([C:20]([OH:22])=[O:21])=[CH:9][NH:10][C:11]=2[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c[nH]c(C(=O)c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(C(=O)c2ccccc2)c1-c1ccccc1

Procedure:
Methyl 4-phenyl-5-benzoylpyrrole-3-carboxylate (345 mg.) was combined with 20 ml. of methanol and 10 ml. of 1N sodium hydroxide and boiled in an open flask for 1 hour. The aqueous residue was cooled, extracted with ethyl acetate, acidified with conc. hydrochloric acid, and product recovered by filtration. Recrystallization from tetrahydrofuran/hexane afforded purified 4-phenyl-5-benzoylpyrrole-3-carboxylic acid [63 mg., m.p. 285°-287° C. (dec.)].
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[CH3:16][C:7]1[C:6]2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[C:10]=2[N:9]2[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=12
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1cccnc1
Product: Cc1c2n(c3c(-c4cccnc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, white solid (60 mg, 79%), MS (ISN) m/z=301.4 [(M−H)+], mp 273° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available pyridin-3-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([C@@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@H:9]1[CH2:15][CH2:16][O:17][Si](C(C)(C)C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([C@@H:8]1[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@H:9]1[CH2:15][CH2:16][OH:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)O[C@@H](CCO[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H](CCO)[C@H](Cc2ccccc2)O1
Reaction time: 5 h
Yield: 94.2 %

Procedure:
To a stirred solution of (2-((4S,5S)-5-benzyl-2,2-dimethyl-1,3-dioxolan-4-yl)ethoxy)(tert-butyl)dimethylsilane (Preparation example 240, 11.5 g, 32.80 mmol) in THF (115 mL) was slowly added tetrabutylammonium fluoride (TBAF, 1.0M in THF, 48.8 mL, 48.8 mmol) at room temperature. The mixture was stirred for 5 h. The resulting mixture was diluted with EtOAc, washed with water, dried over anhydrous magnesium sulfate, filtered and concentrated. The crude compound was purified by a silica gel column to produce the title compound (7.3 g, 80˜95%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].Cl.[CH3:13][NH:14][O:15][CH2:16][C:17]([OH:19])=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([N:14]([CH3:13])[O:15][CH2:16][C:17]([OH:19])=[O:18])=[S:11]
Reactant: CNOCC(=O)O
Reactant: Cc1ccc(C)c(N=C=S)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(NC(=S)N(C)OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A mixture of 2,5-dimethylphenyl-isothiocyanate (16.3 g), N-methyl aminooxy acetic acid hydrochloride (15.55 g), triethylamine (30 g) and chloroform (250 mL) was heated at reflux for one hour, stirred at ambient temperature for one hour, then evaporated to dryness. The residue was dissolved in ethyl acetate (500 mL) and washed with 2N HCl (2×200 mL) then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness affording (25 g) of [[[[(2,5-dimethylphenyl)amino]thioxomethyl]methylamino]oxy]acetic acid as an oil. 1H-NMR (DMSO-d6; 300 Mhz) δ13.25 (br s, 1H), 10.08 (s, 1H), 7.15-6.94 (m, 3H), 4.62 (s, 2H), 3.52 (s, 3H), 2.24 ppm (s, 3H and 2.10 ppm (s, 3H). The acid (24.1 g) was dissolved in benzene (250 mL). Phosphorus pentachloride (18.7 g) was added in portions. The mixture was heated at reflux for one half hour then evaporated to dryness. The residue was dissolved in ethyl acetate (600 mL) and washed with sodium bicarbonate saturated solution (2×300 mL) then with water (300 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residual oily substance crystallized upon standing. The solid mass was stirred in methanol (100 mL). The solid was collected by filtration and air dried to give the title compound (11.2 g), m.p. 104-106° C. Mass spectrum (El, M.+) m/z 250. 1H-NMR (CDCl3; 400 MHz) δ7.21-7.17 (m, 2H), 6.92 (s, 1H), 4.84 (ABq, 2H), 3.75 (s, 3H), 2.35 (s, 3H), and 2.12 ppm (s, 3H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].CN(C)P(=O)(N(C)C)N(C)C.[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1.[Cl-].[NH4+]>CCCCCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.O1CCCC1>[Br:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH:1][CH2:2][CH2:3][CH3:4])=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: [Li]CCCC
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCC=Cc1ccc(Br)cc1
Temperature: -80 °C
Yield: 82 %

Procedure:
52 ml (83.2 mmols) of a 1.6M n-butyllithium solution in hexane are added to a suspension, cooled to -10° C., of 34 g (85.1 mmols) of n-butyltriphenylphosphonium bromide in 150 ml of tetrahydrofuran. After 20 minutes' reaction, the whole is cooled to -80° C. and 50 ml of hexamethylphosphoric triamide are added, as well as 10 g (54 mmols) of 4-bromobenzaldehyde dissolved in 40 ml of tetrahydrofuran. After returning to room temperature and hydrolysis with a saturated ammonium chloride solution, the reaction mixture is extracted with ether. Customary treatment of the organic phase yields 10 g of the expected compound after purification by chromatography on a silica column (eluent: petroleum ether).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:13])[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:14]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)#[N:15]
Reactant: Nc1ccc2ncccc2c1
Reactant: C[C@@H](Nc1cnc(C#N)c(Cl)n1)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Reaction time: 20 h
Yield: 10.5 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)propanamide (97 mg, 0.430 mmol), 6-aminoquinoline (62 mg, 0.430 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg). The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg, 0.045 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (14 mg). MS 352.58 (M+H); UV 202.9, 265.2, 297.2, 357.9 nm; t 0.335 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2([CH2:17][CH2:18][C:19]([OH:21])=O)[S:16][CH2:15][CH2:14][CH2:13][S:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:37]([NH2:49])[CH2:38][C:39]1[CH:48]=[CH:47][C:44]([O:45][CH3:46])=[C:41]([O:42][CH3:43])[CH:40]=1>O1CCCC1>[CH3:43][O:42][C:41]1[CH:40]=[C:39]([CH:48]=[CH:47][C:44]=1[O:45][CH3:46])[CH2:38][CH2:37][NH:49][C:19](=[O:21])[CH2:18][CH2:17][C:11]1([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[S:12][CH2:13][CH2:14][CH2:15][S:16]1
Reactant: COc1ccc(C2(CCC(=O)O)SCCCS2)cc1OC
Reactant: COc1ccc(CCN)cc1OC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CCNC(=O)CCC2(c3ccc(OC)c(OC)c3)SCCCS2)cc1OC
Reaction time: 3 h

Procedure:
13.2 g of 2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionic acid, 4 g of triethylamine and 180 ml of tetrahydrofuran are cooled to 0° C. and treated dropwise within 10 minutes with 5.44 g of chloroformic acid isobutyl ester in 80 ml of tetrahydrofuran. The mixture is then held at room temperature for 3 hours and treated at 0° C. with 7.25 g of homoveratrylamine in 40 ml of tetrahydrofuran. The suspension is left to stand at 3° C. for 48 hours, then evaporated, treated with water and extracted with ether/methylene chloride (3:1). The ethereal extracts are washed with water, sodium bicarbonate solution, 1-N tartaric acid and water. The organic phase is dried over magnesium sulphate and evaporated. The residue is crystallized from methylene chloride/ether at 0° C. There is obtained N-(3,4-dimethoxyphenethyl)-2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionamide of melting point 135°-136° C.
Reaction SMILES: C(O[C:4](=O)[CH2:5][N:6]=C(C1C=CC=CC=1)C1C=CC=CC=1)C.[H-].[Na+].Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.CI.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.Cl>[Cl:30][C:29]1[C:24]([CH:5]([CH3:4])[NH2:6])=[N:25][CH:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(N)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
N-(diphenylmethylene)glycine ethyl ester (2.25 g) was added to a suspension of sodium hydride (0.74 g of 60% oil dispersion) in 20 mL of dry N,N-dimethylformamide at room temperature, resulting in vigorous gas evolution. After stirring at room temperature for five minutes, 2 g of 2,3-dichloro-5-trifluoromethylpyridine was added, followed by stirring at room temperature for 1 hour. Then 0.80 mL of methyl iodide was added followed by stirring at room temperature overnight. The reaction mixture was poured onto ice water, extracted with diethyl ether (2×), and distilled under vacuum to remove the solvent leaving an oil. The oil was then refluxed in 6 N HCl overnight. The reaction mixture was cooled to room temperature, made basic with solid sodium carbonate and extracted with diethyl ether (2×). The combined extracts were dried over magnesium sulfate and distilled under vacuum to remove the solvent, leaving 1.5 g of an oil. 1H NMR (CDCl3; 300 MHz) δ 1.4 (d, 3H, J is 6.6 Hz), 4.6 (bs, 1H), 7.88 (m, 1H), 8.75 (bs, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([CH:8]([S:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]2OCO[C:19]=2[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:9])([OH:7])=O.[CH3:26]COCC>N1C=CC=CC=1>[CH3:9][C@@H:8]1[S:10][C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH3:26])=[CH:21][C:22]=2[C:5]1=[O:7]
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)SC(C)C(=O)O
Reactant: CCOCC
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1Cc2ccc(C)cc2C(=O)[C@H](C)S1
Temperature: 25 °C
Yield: 62 %

Procedure:
Thionyl chloride (16.4 g) and pyridine (3 drops) were successively added dropwise to a solution of methyl 2-(1-carboxyethyl)thio-3-(3,4-methylenedioxyphenyl)propionate (26.0 g) in ether (250 ml), followed by stirring for an hour at room temperature and for an hour under reflux. The mixture was concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (50 ml) and the resultant solution was added dropwise to a mixture of aluminum chloride (AlCl3)(27.0 g) and dichloromethane (200 ml) under ice-cooling. After stirring for two hours under ice-cooling, the mixture was poured into ice-water. The dichloromethane layer was separated, washed with water, dried (MgSO4) and distilled to remove the solvent. The residual oil was dissolved in methanol (250 ml), to which a solution of sodium methoxide in methanol (28%, 10 ml) was added. The mixture was stirred for 1.5 hours at room temperature, to which 2N--HCl (250 ml) was added. The precipitated crystals was collected by filtration, affording methyl trans-4,7-dimethyl-5-oxo-1,2,4,5 -tetrahydro-3-benzothiepine-2-carboxylate (15.0 g, 62%). Recrystallization from ethyl acetate-hexane gave colorless prisms.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19](O)=[O:20])=[CH:5]2.[NH2:22][C:23]1[CH:24]=[C:25]2[CH:31]=[CH:30][NH:29][C:26]2=[N:27][CH:28]=1>>[NH:29]1[C:26]2=[N:27][CH:28]=[C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)=[O:20])[CH:24]=[C:25]2[CH:31]=[CH:30]1
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: Nc1cnc2[nH]ccc2c1
Product: O=C(Nc1cnc2[nH]ccc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 78.7 %

Procedure:
The process is performed according to a method similar to that described in Example 1.3 starting with 0.4 g (1.39 mmol) of 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid prepared in step 1.1 and 0.22 g (1.67 mmol) of 5-amino-1H-pyrrolo[2,3-b]pyridine (Synthesis 2005, 15, 2503). 0.44 g of the expected product is thus isolated in the form of a white solid.