Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2].C(N(CC)CC)C.[CH2:30]([OH:32])[CH3:31]>>[C:1]([N:3]=[C:4]([O:32][CH2:30][CH3:31])[NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])#[N:2]
Reactant: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reactant: CCO
Solvent: CCN(CC)CC
Product: CCOC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O

Procedure:
A mixture of trans-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.48 g) and triethylamine (0.635 ml) in ethanol (5.0 ml) was stirred under reflux for 7 hours. The solvent was removed under reduced pressure. The residue was extracted with ethyl acetate (15 ml), and washed successively with 5% hydrochloric acid (15 ml) and saturated aqueous solution of sodium chloride (15 ml). The organic solution was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (17 g), eluting with a mixture of methanol and chloroform (1:50 V/V). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of ethanol 1.5 ml) and n-hexane (3 ml) to give trans-4-(3-cyano-2-ethyl-1-isoureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.22 g).
Reaction SMILES: Cl.Cl.[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[CH:9]([NH2:22])[CH2:8][CH:7]1[CH3:23])(=[O:5])[CH3:4].CCN(C(C)C)C(C)C.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=1>CN1C(=O)CCC1>[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[CH:13][CH:14]=2)[CH:9]([NH:22][C:34]2[N:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)[CH2:8][CH:7]1[CH3:23])(=[O:5])[CH3:4]
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2C(N)CC1C
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2C(Nc2ccc(C#N)cn2)CC1C
Temperature: 25 °C
Yield: 11 %

Procedure:
A solution of 1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine di-hydrochloride (for a preparation see intermediate 61) (85 mg, 0.299 mmol) in NMP (2 mL) was treated with DIPEA (0.209 ml, 1.196 mmol), then 6-chloro-3-pyridinecarbonitrile (49.7 mg, 0.359 mmol) and the resulting mixture was heated at 200° C. for 30 min under microwave irradiation, then cooled to room temperature and the solution purified by MDAP to give 6-{[1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]amino}-3-pyridinecarbonitrile (12.2 mg, 0.032 mmol, 11% yield) as a beige solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:36])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:27]3=[C:28]4[C:17]([C:18]5[C:29]6[C:22](=[CH:23][CH:24]=[CH:25][C:26]3=6)[CH:21]=[CH:20][CH:19]=5)=[CH:16][CH:15]=[CH:14][C:13]4=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Br-].[Br-].[Br-].B.O>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([P:9](=[O:36])([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:10]2[C:27]3=[C:28]4[C:17]([C:18]5[C:29]6[C:22](=[CH:23][CH:24]=[CH:25][C:26]3=6)[CH:21]=[CH:20][CH:19]=5)=[CH:16][CH:15]=[CH:14][C:13]4=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(P(=O)(c2ccccc2)c2ccc3cccc4c5cccc6cccc(c2c34)c65)cc1
Agent: B
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: O=P(c1ccccc1)(c1ccc(O)cc1)c1ccc2cccc3c4cccc5cccc(c1c23)c54
Reaction time: 18 h
Yield: 77 %

Procedure:
4-Methoxyphenylphenylperylenylphosphine oxide (400 mg, 0.83 mmol) was dissolved in 30 mL of dichloromethane, and borane tribromide (2.5 mL, 2.5 mmol, 4 eq) was added dropwise to the solution at −78° C. After stirring for 18 hours, 10 mL of H2O was added to the mixture to terminate the reaction. Reddish brown precipitates thus formed were subjected to suction filtration. The crystals obtained were dried overnight in a drying pistol to give reddish brown crystals (yield 77%). The crystals obtained were identified by 1H-NMR, 31P-NMR, IR, ESI-MS and UV.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH2:18][OH:19].C(N(CC)CC)C>ClCCl>[CH3:11][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH:18]=[O:19]
Reactant: CN1CCCCC1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCCCC1C=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.5 %

Procedure:
Dimethyl sulfoxide (3.3 mL, 46 mmol) was dissolved in 15 mL of dichloromethane in a dry ice bath, followed by dropwise slowly addition of oxalyl chloride (2.6 mL, 31 mmol). After stirring for 45 minutes, a solution of (1-methyl-2-piperidyl)methanol 6a (1 g, 7.74 mmol) in 5 mL of dichloromethane was added dropwise to the solution. The reaction mixture was stirred for 45 minutes, then added with triethylamine (7.2 mL, 52 mmol), and stirred for 10 minutes, then warmed up to room temperature and stirred for 1 hour. The reaction mixture was washed with water (20 mL) and saturated brine (20 mL) successively. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure then the resulting residue was purified by alkaline alumina column chromatography with elution system A to obtain the title compound 1-methylpiperidine-2-carbaldehyde 6b (300 mg, yield 31.0%) as a brown oil, which was directly used in the next step without purification.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[CH2:12][NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([O:23][C:24](=O)[C:25]3C=CC=CC=3)[CH:20]=[CH:21][CH:22]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35](OC1C=CC=CC=1NCCN)(C)C>>[CH:24]([O:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]1[CH:10]=[C:9]([C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:8])[CH:34]=[CH:33][CH:32]=1)([CH3:35])[CH3:25]
Reactant: CC(C)Oc1ccccc1NCCN
Reactant: O=C(Oc1cccc(OCCNCc2cccc(C(=O)N3CCCCC3)c2)c1)c1ccccc1
Product: CC(C)Oc1cccc(OCCNCc2cccc(C(=O)N3CCCCC3)c2)c1

Procedure:
Benzoic acid 3-{2-[3-(piperidine-1-carbonyl)-benzylamino]-ethoxy}-phenyl ester. The title compound was prepared as in Example 1, steps D and E, substituting benzoic acid 3-(2-amino-ethoxy)-phenyl ester for N1-(2-isopropoxy-phenyl)-ethane-1,2-diamine in step E. MS (ESI): mass calculated for C28H30N2O4, 458.22; m/z found, 459.2 [M+H]+, 481.2 [M+Na]+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[C:20]([CH3:22])[CH:21]=2)[CH:18]=[C:17]([CH:23]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH:30][CH2:23][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[C:20]([CH3:22])[CH:21]=[C:12]([O:11][CH:8]3[CH2:7][CH2:6][CH:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH:18]=1
Reactant: COC(=O)CN
Reactant: Cc1cc(OC2CCC(C(C)(C)C)CC2)cc2ccc(C=O)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCc1ccc2cc(OC3CCC(C(C)(C)C)CC3)cc(C)c2c1
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of 6-(4-tert-butyl-cyclohexyloxy)-8-methyl-naphthalene-2-carbaldehyde (50 mg, 0.15 mmol), glycine methyl ester, hydrochloride (27 mg, 0.22 mmol) and diisopropylethylamine (DIEA) (34 uL) in 1,2-dichloroethane (2 mL) was stirred for 1 hour at room temperature. Then sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added and stirred for 3 hrs. The reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate aqueous, dried over MgSO4, filtered, and concentrated. The crude was purified via silica gel column chromatography eluted 0-5% MeOH in methylene chloride to give the light brown solid (53 mg, yield: 86%). ESI-MS: 420.30 (M+23)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH:11]1[CH2:14][N:13]([C:15]2[CH:20]=[C:19]([N:21]3[C:25]([CH3:26])=[N:24][C:23]([CH3:27])=[N:22]3)[N:18]=[C:17]([CH3:28])[N:16]=2)[CH2:12]1)=O>C(O)(=O)C>[CH3:27][C:23]1[N:24]=[C:25]([CH3:26])[N:21]([C:19]2[N:18]=[C:17]([CH3:28])[N:16]=[C:15]([N:13]3[CH2:14][CH:11]([C:9]4[NH:8][C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[N:1]=4)[CH2:12]3)[CH:20]=2)[N:22]=1
Reactant: Cc1nc(N2CC(C(=O)Nc3ccccc3N)C2)cc(-n2nc(C)nc2C)n1
Solvent: CC(=O)O
Product: Cc1nc(N2CC(c3nc4ccccc4[nH]3)C2)cc(-n2nc(C)nc2C)n1
Temperature: 100 °C

Procedure:
Compound 107-3 (175 mg, 0.462 mmol) was dissolved in acetic acid (10 mL) and heated at 100° C. for 18 h. The mixture was cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (0-100% EtOAc (containing 10% MeOH)/hexanes), providing Example 107 as a light yellow solid. 1H NMR: (400 MHz, CDCl3) δ 9.93 (br s, 1H), 7.62-7.60 (m, 2H), 7.29-7.26 (m, 2H), 6.30 (s, 1H), 4.62-4.52 br m, 2H), 4.40-4.30 (br m, 3H), 2.84 (s, 3H), 2.50 (s, 3H), 2.34 (s, 3H) ppm; MS: m/z=361.3 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.C(OCC)(=O)NN.BrC1C=CC(C2C(C)=[CH:32][C:33]3[N:34]([C:36](=[O:39])NN=3)[N:35]=2)=CC=1>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]3[N:10]([C:36](=[O:39])[N:34]([CH2:33][CH3:32])[N:35]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)nnc1-c1ccc(Br)cc1
Reactant: Cc1cc2n[nH]c(=O)n2nc1-c1ccc(Br)cc1
Agent: CCOC(=O)NN
Solvent: CCCCO
Product: CCn1nc2cc(C)c(-c3ccc(Br)cc3)nn2c1=O

Procedure:
A mixture comprising 328 g. of 3-(p-bromophenyl)-6-chloro-4-methylpyridazine (U.S. Pat. No. 4,092,311), 242 g. of ethyl carbazate and 2 liters of butanol is stirred at reflux for 4 days, then cooled in an ice bath. The resulting solid is collected by filtration and air dried, giving 269 g. of 6-(p-bromophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one.
Reaction SMILES: [O:1]1CC[CH2:3][CH2:2]1.[H-].[Na+].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=1[CH3:19].Cl>C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.O.C(O)C.C(OCC)(=O)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH2:17][C:2](=[O:1])[CH3:3])=[CH:12][C:11]=1[CH3:19]
Reactant: COc1ccc(C(C)=O)cc1C
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C(=O)CC(C)=O)cc1C

Procedure:
At room temperature, to tetrahydrofuran 50 ml was added 55% sodium hydride 3.07 g and ethyl acetate 5.90 g and the resulting mixture was stirred for a half hour. Then, thereto was added 1 (4 methoxy-3-methylphenyl)-ethanone (described in Reference Preparation example 48) 5.50 g, dibenzo-18-crown-6 0.024 g and ethanol 1 ml and the resulting mixture was stirred with heating under reflux for six hours. To the reaction mixture was added water and the resulting mixture was acidified with aqueous 10% hydrochloric acid solution and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 1-(4-methoxy-3-methyl-phenyl)-butane-1,3-dione 6.50 g.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([O:17][CH:18]([CH3:20])[CH3:19])[N:12]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.CC1(C)C(C)(C)OB([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([NH2:45])[CH:40]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.O>[CH3:20][CH:18]([O:17][C:13]1[N:12]=[C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][CH:3]=[C:2]3[C:39]2[CH:44]=[CH:43][N:42]=[C:41]([NH2:45])[CH:40]=2)[CH:16]=[N:15][CH:14]=1)[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cncc(OC(C)C)n4)ccc32)cc1
Reactant: CC1(C)OB(c2ccnc(N)c2)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(-c4ccnc(N)c4)c3c2)n1
Temperature: 130 °C

Procedure:
A solution of 3-iodo-5-(6-isopropoxypyrazin-2-yl)-1-tosyl-1H-indole (0.060 g, 0.11 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (39, 0.17 mmol), Potassium Phosphate (0.072 g, 0.34 mmol), Pd2 dba3 (5 mg, 6 μmol), X-Phos (5 mg, 0.011 mmol), and dioxane/water (2/1, 1.5 mL) was heated in a microwave at 125° C. for 10 min. The solution was cooled, the aqueous layer was removed, and the organic layer was purified by prep HPLC (66-95% ACN/water/0.1% TFA). The resulting product was dissolved in dioxane (1 mL), 1M NaOH (0.2 mL) was added, and the mixture was heated in a microwave at 130° C. for 10 min. The resulting solution was purified by preparative HPLC (10-90% ACN/water/0.1% TFA) to give 4-(5-(6-(1-methylethoxy)-2-pyrazinyl)-1H-indol-3-yl)-2-pyridinamine. MS (ESI, pos. ion) m/z: 346 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:8]=1[CH:9]=[N:10]O>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][C:8]=1[C:9]#[N:10]
Reactant: COc1ccc(Oc2ccccc2)cc1C=NO
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc(Oc2ccccc2)cc1C#N

Procedure:
Thionyl chloride (11.9 ml, 163 mmol) was added under a nitrogen atmosphere to a suspension of 2-methoxy-5-phenoxybenzaldehyde oxime (3.96 g, 16.3 mmol) in 75 ml of benzene. There was a slight exotherm and the mixture turned yellow. The reaction was heated to reflux temperature over 1 hour and at reflux temperature for an additional hour. The solvent and excess thionyl chloride were removed under reduced pressure to give 2-methoxy-5-phenoxybenzonitrile as a light tan crystalline solid (3.66 g, 100% ), mp 88°-89° C.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Yield: 85.9 %

Procedure:
3-nitrophthalic anhydride (0.79 g, 0.0041 mol) and p-aminobenzoic acid (0.56 g, 0.0041 mol) were refluxed as above overnight. Concentration of the solution under vacuum by rotary evaporator and crystallisation of the product from EtOH/H2O yielded 1.1 g (68%) of 125 as a vibrant light yellow powder: mp=338–340° C.; Rf 0.76 (A): Rf 0.89 (C): Rf 0.66 (D): R (cm−1): 2750–3125 (OH), 3091 (C═CH), 2671 (C—H), 1782 (C═O), 1736 (C═O), 1693 (C═O), 1610 (C═C), 1585 (C═C), 1529 (N═O), 1513 (C═C), 1433 (C═C), 1378 (C—O), 1360 (N═O), 1291 (C—O), 766 (C═CH); MS m/z (rel intensity) 311 (100), 267 (25), 191 (15).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH2:10]Br)[CH:3]=1.[C-:12]#[N:13].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O.C(Cl)Cl>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH2:10][C:12]#[N:13])[CH:3]=1
Reactant: COc1cnc(CBr)cc1Br
Reactant: [C-]#N
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1cnc(CC#N)cc1Br
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of 4-bromo-2-bromomethyl-5-methoxy-pyridine (Step AL2) (1.2 g, 4.3 mmol), KCN (417 mg, 6.4 mmol) and aliquat 336 (35 mg, 0.085 mmol) in H2O was stirred at 50° C. for 2 h. The reaction mixture was dissolved in CH2Cl2, extracted with a saturated aqueous solution of NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane/EtOAc, 100:0→1:1). tR: 3.83 min (HPLC 7).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH3:18])[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C1(OC2C=CC=CC=2)C=CC=CC=1>[Pd].C(OCC)C>[N:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([NH:17][CH3:18])[CH:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNc1cc(N2CCc3ccccc32)cc(C)n1
Agent: [Pd]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CNc1cc(-n2ccc3ccccc32)cc(C)n1
Yield: 94.1 %

Procedure:
A mixture of 4-(1-indolinyl)-6-methyl-2-(methylamino)pyridine (0.45 g, 1.88 mM), 30% w/w palladium on charcoal (0.045 g) and diphenyl ether (10 ml) was heated under reflux for 45 minutes. The mixture was cooled. Diethyl ether (50 ml) was added and the catalyst removed by filtration through diatomaceous earth. The filter cake was washed with diethyl ether (50 ml). The filtrate and washings were concentrated under reduced pressure. The yellow solid obtained was further purified by flash chromatography (Merck 9385 silica, 100 g) eluting with diethyl ether to give 4-(1-indolyl)-6-methyl-2-methylaminopyridine as a solid (0.42 g, 90% yield), m.p. 156°-158° C.; NMR (CDCl3): 2.45(3H,s,CH3), 2.9-3.0(3H,d,NHCH3), 4.75-4.85(1H,br, NH), 6.3(1H,s, pyridine-3H), 6.6-6.7(2H, complex, pyridine-5H and indole-3H), 7.15-7.4(3H, complex, indole-2H and aromatic), 7.65-7.75(2H, complex, aromatic).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(#N)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.O>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][CH3:16])[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CSc1ccccc1B(O)O
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: O
Solvent: CC#N
Product: CSc1ccccc1-c1nc2cc(F)cc(F)c2c(Cl)c1C

Procedure:
Prepared according to procedure F by stirring 2,4-dichloro-5,7-difluoro-3-methylquinoline (550 mg, 2.22 mmol), 2-(methylthio)phenylboronic acid (484 mg, 2.88 mmol), sodium carbonate (705 mg, 6.65 mmol), Pd(PPh3)4 (128 mg, 0.11 mmol), acetonitrile (5.2 mL), and water (1.3 mL) at 100° C. in a microwave reactor for 1 h. Purification by column chromatography (silica gel, 0-20% EtOAc in hexanes) gave 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylthio)phenyl)quinoline as a white amorphous solid. Mass Spectrum (ESI) m/e=336.1 (M+1).
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[C:12]([CH3:26])[CH:13]=[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:24][CH3:25])[C:9]2=[N:8][C:7]=1[CH3:27])(OCC)=[O:2].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[CH3:27][C:7]1[N:8]=[C:9]2[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:24][CH3:25])=[CH:13][C:12]([CH3:26])=[CH:11][N:10]2[C:6]=1[CH2:1][OH:2]
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cccc3CC)cc(C)cn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(C)c1CNc1cc(C)cn2c(CO)c(C)nc12
Yield: 40.9 %

Procedure:
3-Carboethoxy-2,6-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo[1,2-a]pyridine (1.0 g 2.8 mmol) was added to tetrahydrofuran (25 ml) and was stirred at +5° C. Lithium aluminum hydride (0.5 g, 13 mmol) was added in portions during 1.5 h so that the temperature remained below +10° C. After stirring the mixture at room temperature for an additional 1 h, 0.5 ml of water was added dropwise, followed by 0.5 ml of 15% sodium hydroxide and then 1.5 ml of water. The solids were removed by filtration and washed thoroughly with tetrahydrofuran and methylene chloride. The filtrate and washings were combined and dried and the solvents were removed under reduced pressure. The residue was solved in methylene chloride and washed with water. The organic layer was separated, dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethylacetate:methylene chloride (1:1) as eluent. Crystallization from petroleum ether:diethyl ether (1:1) gave 0.37 g (41%) of the title compound.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[O:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.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>[O:21]1[CH:25]=[CH:24][C:23]([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)=[CH:22]1
Reactant: OB(O)c1ccoc1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: OCCCO
Product: FC(F)(F)c1cc(-c2ccoc2)c2c(c1)ncn2-c1ccccc1
Yield: 53.6 %

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (0.5 g, 1.25 mmol), 3-furane boronic acid (0.2 g, 1.87 mmol), 1,3-propanediol (0.45 ml, 6.2 mmol), potassium carbonate (0.86 g, 6.2 mmol) and bis(triphenylphosphin)palladium dichloride (50 mg, 0.07 mmol) in a mixture of dimethoxyethane (10 ml) and water (15 ml) was stirred at reflux in a nitrogen atmosphere for 30 min. The cooled reaction mixture was partitioned between ethyl acetate and water and the organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The residue was triturated in diethyl ether to afford the title product as an off-white solid (0.22 g, 54%) m/z, 329.1 (M+H)+.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1]([N:4]1[C:5]2[C:6](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]1=[O:20])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)Nc1ccccc1C=O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2ccccc2n(C(C)C)c1=O
Yield: 163.7 %

Procedure:
A solution of 20.0 g of 2-isopropylaminobenzaldehyde, 29.4 g of diethyl malonate, 10 ml of piperidine, 10 ml of acetic acid and 500 ml of toluene was heated to reflux for 13 hours. The reaction solution was washed with water and then with saturated sodium hydrogencarbonate aqueous solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off to give 52 g of ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate as the crude product.