Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH2:34])=[CH:29][C:28]=3[C:35]([F:38])([F:37])[F:36])=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(Cl)Cl.CC(N(C)C)=O.[F:49][C:50]1[CH:55]=[CH:54][C:53]([C:56](Cl)=[O:57])=[CH:52][N:51]=1>>[CH3:1][O:2][C:3](=[O:39])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[C:31]([F:33])[C:30]([NH:34][C:56]([C:53]4[CH:52]=[N:51][C:50]([F:49])=[CH:55][CH:54]=4)=[O:57])=[CH:29][C:28]=3[C:35]([F:37])([F:38])[F:36])=[CH:25][CH:26]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(N)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(-c3cc(F)c(NC(=O)c4ccc(F)nc4)cc3C(F)(F)F)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.9 %

Procedure:
To a solution of ((S)-1-{(S)-2-[4-(4′-amino-5′-fluoro-2′-trifluoromethyl-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (128 mg, 0.234 mmol; Preparation 39) in DCM (3 mL, 47 mmol) and DMA (0.3 mL, 3 mmol) was added 2-fluoropyridine-5-carbonyl chloride (37 mg, 0.234 mmol), and the resulting solution was stirred at RT overnight. The reaction mixture was concentrated by rotary evaporation to give the monoHCl salt of the title intermediate as a brownish oil (163 mg), which was used without further purification. (m/z): [M+H]+ calcd for C33H31F5N6O4 671.23 found 671.7.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH:6]([NH2:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:15]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH3:2])=[O:16])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CC(N)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid methyl ester hydrochloride (1.50 g, 6.1 mmol) and sodium carbonate (90.65 g, 6.1 mmol) in 40 mL of water was added N-carboethoxyphthalimide (1.34 g, 6.1 mmol) in 12 mL of acetonitrile. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partially concentrated and this mixture was stirred for 72 hours. The resulting slurry was filtered and the solid was washed with copious amount of water. The solid was dried in vacuo (30° C., <1 mm) to afford 1.70 g (50%) of methyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder. mp 65°-66° C.; 1H NMR (DMSO-6, 250 MHz) δ7.83-7.91 (m, 4H), 6.88-7.3 (m, 4H), 5-80 (dd, 1H, J=7.5, 2.5), 372 (S, 3H), 3.54 (3, 3H), 3.2-3.6 (m, 2H); 13C NMR (DMSO-d6) δ170.7, 167.5, 158.7, 134.6, 131.0, 130.5, 128.3, 123.2, 113.9, 55.0, 51.5, 49.4, 35.4. Anal. Calcd for C19H17NO5 : C, 67.25; H, 5.05; N, 4.13; Found: C, 66.96; H, 5.00; N, 4.11.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7](Br)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].C(N(CC)CC)C.[CH3:21][Si:22]([C:25]#[CH:26])([CH3:24])[CH3:23]>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.O>[CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7]([C:26]#[C:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccnc1C#C[Si](C)(C)C
Temperature: 100 °C

Procedure:
A mixture of (2-bromo-pyridin-3-yl)carbamic acid ethyl ester described in Preparation Example S-2 (395 mg, 1.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol), triethylamine (0.25 mL, 1.8 mmol), copper(I)iodide (10 mg, 0.05 mmol) and trimethylsilylacetylene (0.131 mL, 2.4 mmol) was placed in a sealed tube, and heated at 100° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water, which was then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then evaporated, the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2), and the title compound (0.42 g, 1.6 mmol, quantitatively) was obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6]1[O:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])=[N:9][N:10]=1.C1COCC1>>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:8]1[O:7][C:6]([NH:5][CH2:4][CH2:3][OH:2])=[N:10][N:9]=1
Reactant: COC(=O)CNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Solvent: C1CCOC1
Product: OCCNc1nnc(-c2ccncc2Nc2ccc(I)cc2F)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.7 %

Procedure:
To a solution of {5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,3,4]oxadiazol-2-ylamino}-acetic acid methyl ester (400 mg, 0.85 mmol, 1 eq) in THF (5 mL) LiBH4 (37 mg, 1.7 mmol, 2 eq) was added. The reaction mixture was stirred at RT for 20 hrs and then quenched with methanol and then added water. The solvent was partially removed and EtOAc was added. A solid precipitated out that was filtered to give the desired product (190 mg). LC/MS (Method A) [4.48 min; 442(M+1)]
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].[H-].[Na+].Br.Br[CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:23])[CH2:6][O:5][C:4]2=[CH:7][C:8]3[O:9][CH2:10][C:11]4([C:21]=3[CH:22]=[C:3]12)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:12]4=[O:20]
Reactant: BrCc1cccnc1
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(Cc2cccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To a solution of 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.08 g, 0.26 mmol) in DMF (10 mL) was added sodium hydride (0.03 g, 0.78 mmol) slowly at 0° C. After 30 min, 3-(bromomethyl)-pyridine hydrobromide (0.10 g, 0.39 mmol) was added. The mixture was stirred at ambient temperature overnight, quenched with saturated ammonium chloride (10.0 mL). The mixture was extracted with ethyl acetate (3×20.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/1) to give 5,5-dimethyl-1′-(pyridin-3-ylmethyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one as a white solid (0.05 g, 48%), which was treated with 2.0 M HCl in diethyl ether to give the title compound: mp 124-126° C.; 1H NMR (300 MHz, CD3OD) δ 8.96 (br, 1H), 8.82 (br, 1H), 8.62 (d, 1H), 7.3 (t, 1H), 7.32 (td, 1H), 7.23-7.17 (m, 1H), 7.16-7.08 (m, 2H), 6.42 (s, 1H), 6.32 (s, 1H), 5.35-5.14 (m, 2H), 4.93-4.84 (m, 1H), 4.74 (d, 1H), 4.18 (s, 2H), 1.18 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 178.9, 161.6, 161.1, 145.4, 141.3, 141.1, 132.5, 130.1, 128.8, 124.0, 123.9, 120.1, 116.2, 108.8, 92.6, 85.1, 80.2, 57.8, 41.0, 40.5, 26.5, 26.4; MS (ES+) m/z 399.5 (M+1).
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][C:16]1([CH3:30])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)[O:17]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:22][C:20]1([CH3:21])[C:16]([CH3:30])([CH3:15])[O:17][B:18]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:8](=[O:10])[CH3:9])=[N:27][CH:28]=2)[O:19]1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
4-dimethylaminopyridine (17 mg, 0.139 mmol), triethylamine (0.19 mL, 1.36 mmol) and acetic anhydride (153 mg, 1.50 mmol) were added sequentially to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (300 mg, 1.36 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 0.5 h, then diluted with 30 mL of dichloromethane, washed with 50 mL of a saturated aqueous solution of ammonium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give 225 mg of the product.
Reaction SMILES: [C@@:1]12([OH:10])[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[CH:2]2.[F:11][CH:12]([F:30])[C:13]1([C:27]([OH:29])=[O:28])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2.CBr>C(#N)C>[C@@:1]12([OH:10])[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[CH:2]2.[F:30][CH:12]([F:11])[C:13]1([C:27]([O-:29])=[O:28])[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:20][C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: O=C(O)C1(C(F)F)c2ccccc2Oc2ccccc21
Agent: CBr
Agent: CN1[C@@H]2CC=C[C@@]1(O)CC2
Solvent: CC#N
Product: O=C([O-])C1(C(F)F)c2ccccc2Oc2ccccc21

Procedure:
0.6 g (0.002 mol) 4f are taken up in 20 mL acetonitrile and reacted with 1.14 g (0.006 mol) of 50% methyl bromide solution in acetonitrile analogously to step 1.3. Yield: 0.44 g beige crystals (45% of theoretical yield); melting point: 227° C.-228° C.; elemental analysis: calculated: C (58.55), H (4.91), N (2.84); found: C (57.19), H (5.11), N (2.86).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1.S([CH2:40][N+:41]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[K+]>COCCOC.C(O)(C)(C)C>[C:40]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([C:15]2[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:17][N:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=23)=[N:9]1)#[N:41]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: COCCOC
Product: N#CC1CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
To a solution of 3-[2-(2-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (384 mg) and tosylmethyl isocyanide (430 mg) in 1,2-dimethoxyethane (4 ml) was added dropwise a solution of potassium tert-butoxide (448 mg) in a mixture of 1,2-dimethoxyethane and tert-butanol (1:1, 2 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 30 minutes. Then, it was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The crude product was crystallized from diethyl ether to give yellow crystals of 3-[2-(2-cyanocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.12 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1([CH:16]=O)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+].Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:16][C:10]2([F:9])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: O=CC1(F)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC1(CNc2cccc(Br)n2)CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6-bromopyridin-2-amine (3.03 g, 17.50 mmol) was added the crude solution of 4-fluorotetrahydro-2H-pyran-4-carbaldehyde in DCM. To the mixture was added acetic acid (1.002 mL, 17.50 mmol) and sodium triacetoxyborohydride (5.56 g, 26.3 mmol) in portions. The mixture was stirred for 2 hr at ambient temperature. The mixture was diluted carefully with saturated aqueous NaHCO3 solution. The separated aqueous layer was extracted with DCM (1×). The combined organic layers were washed with water (1×), saturated aqueous NaHCO3 solution (1×) and concentrated in vacuo. The solid resulting residue was dissolved in DCM (100 mL) and 3M aqueous HCl (60 mL). The separated organic layer was extracted with 3M aqueous HCl (3×20 mL). The combined acidic layers were washed with DCM (1×). Solid NaHCO3 was added carefully to the acidic solution [Caution: gas development!] until pH>˜8. The aqueous mixture was extracted with DCM (2×) and EtOAc (2×). The combined organic layers were concentrated in vacuo. The resulting residue was dissolved in EtOAc. The solution was washed with 0.3M aqueous HCl, and brine, dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/heptane=5/95 for 3 min, then EtOAc/heptane=5/95 to 30/70 over 15 min, then EtOAc/heptane=30/70] providing 6-bromo-N-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine as a white solid. Yield: 1.82 g. LCMS (m/z): 288.9/291.0 [M+H]+; Retention time=0.84 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=1.[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH2:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:22]1[CH2:26][CH2:25][C@@H:24]([NH:27][C:2]2[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][N:3]=2)[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)nc1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)nc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A mixture of ethyl (2E)-3-(2-chloro-5-pyrimidinyl)acrylate (200 mg), (3R)-1-benzyl-3-pyrrolidinamine (0.244 mL), and N,N-dimethylformamide (5 mL) was stirred for 3 hours at 60° C. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was washed with saturated NaHCO3 and brine, dried over MgSO4, filtered, and evaporated in vacuo to give ethyl (2E)-3-(2-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-pyrimidinyl)acrylate (330 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH:20]=[CH2:19]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1C#N
Temperature: 0 °C
Reaction time: 12 h
Yield: 64.3 %

Procedure:
To a stirred solution of 2-hydroxy-4-nitrobenzonitrile (5.0 g, 30.48 mmol) in DMF (50 mL) was added Cs2CO3 (19.9 g, 60.97 mmol). The mixture was cooled to 0° C., and allyl bromide (4.39 g, 36.58 mmol) was added dropwise. The reaction mixture was stirred for 12 h at 90° C. under nitrogen. The reaction mixture was cooled to rt and concentrated to remove DMF, then EtOAc (50 mL) was added to the residue. The mixture was washed with water (2×30 mL) and brine (30 mL). The organic layer was dried with Na2SO4, and concentrated in vacuo to afford the yellow solid, 2-(allyloxy)-4-nitrobenzonitrile (4 g, 65% yield). LC-MS (M+H)+=205.2 1H NMR (400 MHz, CDCl3) δ ppm 7.87-7.86 (m, 1H), 7.811 (s, 1H), 7.76 (d, 1H, J=8.4 Hz), 6.11-6.01 (m, 1H), 5.56-5.55 (dd, 1H, J=1.6, 3.2 Hz), 5.52 (d, 1H, J=1.6 Hz), 4.79 (d, 2H, J=4.8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>>[C:25]([NH:29][C:18]1[S:19]/[C:15](=[CH:14]\[C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]=[CH:6][C:5]([C:23]#[N:24])=[C:4]3[O:3][CH2:1][CH3:2])/[C:16](=[O:22])[N:17]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NC(C)(C)C)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), tert-butylamine and DIEA to give 6-[2-tert-Butylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-ethoxy-quinoline-3-carbonitrile. LC-MS m/e 381 (MH+).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>COCCOC>[CH:13]1([CH:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:26])=[CH:23][CH:22]=2)[CH3:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(Nc1ccc(C(=O)Cl)cc1)C1CCCC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(NC(C)C2CCCC2)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of 4-(1-cyclopentylethylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield diethyl 4-(1-cyclopentylethylamino)benzoylmalonate.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[CH2:18][CH3:19].[BH4-].[Na+]>CO>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][CH2:17][CH2:18][CH3:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,3-diphenylpropan-1-amine 1 (4.22 g, 20.0 mmol) in MeOH (100 mL) at room temperature was added propionaldehyde (1.16 g, 20.0 mmol) (1.45 mL). The reaction mixture was stirred at room temperature for 3 h and sodium borohydride (1.20 g, 31.7 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, quenched with 5 M NaOH, partially concentrated, and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 2% to 8% MeOH (2 M NH3) in DCM) gave 3,3-diphenyl-N-propylpropan-1-amine 7 as a pale yellow oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:2].I[C:14]1[N:18]2[C:19]3[S:25][CH:24]=[CH:23][C:20]=3[N:21]=[CH:22][C:17]2=[N:16][C:15]=1[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CO.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>[CH3:26][C:15]1[N:16]=[C:17]2[CH:22]=[N:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[N:18]2[C:14]=1[C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=1
Reactant: N#CCc1ccc(B(O)O)cc1
Reactant: Cc1nc2cnc3ccsc3n2c1I
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: [K+]
Solvent: CO
Product: Cc1nc2cnc3ccsc3n2c1-c1ccc(CC#N)cc1
Temperature: 160 °C

Procedure:
A mixture of [4-(cyanomethyl)phenyl]boronic acid (from Aldrich, 9.3 mg, 0.058 mmol), 8-iodo-7-methylimidazo[1,2-a]thieno[3,2-e]pyrazine (12 mg, 0.038 mmol), and potassium carbonate (16 mg, 0.12 mmol), in acetonitrile (0.6 mL) and water (0.2 mL) was degassed. Into the mixture was added tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 0.0019 mmol). The reaction mixture was heated at 160° C. for 10 min in a microwave reactor. The reaction was diluted with methanol, filtered. The filtrate was purified by prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C17H13N4S (M+H)+: m/z=305.1. Found: 305.0. 1H NMR (CDCl3, 400 MHz) δ 9.01 (1H, s), 7.55 (4H, m), 7.49 (1H, d, J=6.0 Hz), 7.14 (1H, d, J=6.0 Hz), 3.93 (2H, s), 2.48 (3H, s) ppm.
Reaction SMILES: [ClH:1].Br[C:3]1C=C(NC)C(N)=C[CH:8]=1.[Na].[N:13]1([C:19]2[N:20]=[C:21](CC(O)=O)[NH:22][C:23](=O)[CH:24]=2)[CH2:18]COC[CH2:14]1>CN(C=O)C.N1C=CC=CC=1>[ClH:1].[CH3:18][N:13]([CH3:14])[CH2:19][CH2:24][CH2:23][N:22]=[C:21]=[N:20][CH2:3][CH3:8]
Reactant: O=C(O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CNc1cc(Br)ccc1N
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCN=C=NCCCN(C)C

Procedure:
In a round-bottom flask, the 4-bromo-N2-methylbenzene-1,2-diamine hydrochloride prepared above (1.2 g) is placed in a mixture of DMF (10 ml) and pyridine (10 ml) with magnetic stirring, and then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (968 mg) and then the sodium salt of (4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid, obtained in stage 2 of Example 1 (1.2 g) are added. The mixture thus obtained is stirred at ambient temperature (20° C.) overnight. After evaporation of the reaction medium, glacial acetic acid (20 ml) is added and the resulting mixture is brought to reflux (90 min). The reaction medium is concentrated, and taken up in dichloromethane and water at pH 8 (2N sodium hydroxide), so as to form a solid which is filtered off and washed with dichloromethane. The solid obtained is dissolved in methanol, adsorbed onto silica (7 g) and purified by chromatography. Purification is carried out on a silica column (50 g), elution being carried out with a mixture of dichloromethane and 9/1 dichloromethane/MeOH (with CV=75 ml; gradient: 4 CV DCM; 4 CV of 0 to 16% 9/1 DCM/MeOH; 8 CV of 16 to 20% 9/1 DCM/MeOH; 1 CV of 20 to 30% 9/1 DCM/MeOH). The fractions containing the expected compound are combined and evaporated under reduced pressure. 900 mg of 2-[(6-bromo-1-methyl-1H-benzimidazol-2-yl)methyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are isolated, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][N:22]=[C:23]=[O:24]>C1CCCCC1>[CH3:1][C:2]1([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][N:3]1[C:23]([NH:22][CH3:21])=[O:24])=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CCOC(=O)CC1(C)NCCc2c1[nH]c1ccccc21
Reactant: CN=C=O
Solvent: C1CCCCC1
Product: CCOC(=O)CC1(C)c2[nH]c3ccccc3c2CCN1C(=O)NC

Procedure:
10.9 g (0.04 mol) of ethyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-1-acetate are suspended in 200 ml of cyclohexane. 3 ml (0.04 mol) of methyl isocyanate are added. The mixture is heated under reflux for 1 hour. It is allowed to cool overnight in a refrigerator. The precipitate is filtered off. The product is recrystallised from ethanol.