Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[N:15]([CH3:14])[CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1Cl
Reactant: CNC1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)cc(N(C)C2CCOCC2)c1Cl
Temperature: 100 °C
Yield: 14.3 %

Procedure:
To a stirred solution of methyl 3,4,6-trichloropyridine-2-carboxylate (600 mg, 2.50 mmol) in DMF (12 ml) was added TEA (696 μl, 4.99 mmol) followed by N-methyloxan-4-amine (287 mg, 2.50 mmol) and the reaction mixture was heated at 100° C. for 20 h. The reaction mixture was then cooled to room temperature and poured onto water (100 ml), followed by extraction of the product into EtOAc (3×100 ml), washing of the combined organics with brine (50 ml), drying with Na2SO4 and evaporation. The crude product was then purified over a 10 g silica Isolute column eluting with a gradient of 0% to 60% EtOAc in heptane to afford the title compound as a white solid (114 mg, 14%). LC-MS 100%, 1.91 min (3.5 minute LC-MS method), m/z=319.3/320.9, 1H NMR (500 MHz, Chloroform-d) δ 6.87 (s, 1H), 4.15-4.00 (m, 2H), 3.98 (s, 3H), 3.93-3.71 (m, 1H), 3.54-3.24 (m, 2H), 2.82 (s, 3H), 1.94 (dd, J=12.1, 4.7 Hz, 2H), 1.70 (d, J=10.2 Hz, 2H). (br. s., 4H) 1.48 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH3:10])=[CH:4][CH:3]=1.[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][N:13]([CH2:36][CH2:35][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH3:10])=[CH:27][CH:28]=1
Reactant: OCCN1CCCCC1
Reactant: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(CC=Cc1ccc(Cl)cc1)CCN(CCN1CCCCC1)S(=O)(=O)c1cccc2cnccc12
Yield: 74.9 %

Procedure:
To a solution of 0.39 g of the amorphous compound obtained in Example 190, 0.145 g of 1-piperidinethanol and 0.369 g of triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a solution of 0.245 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. The mixture was stirred for 2 hours and evaporated to remove the solvent under a reduced pressure, and resulting residue dissolved in 30 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid. The aqueous layer was alkallized with sodium bicarbonate and extracted three times with 10 ml of ehtyl acetate, and the organic extract was dried over magnesium sulfate and evaporated to remove the solvent at a reduced pressure. The resulting residue was applied to a silica gel column and eluted with 2% methanol in chloroform, to obtain 0.37 g of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Br)c2)CC1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A solution of 3-bromo-5-iodopyridine (13.0 g, 45.8 mmol), tert-butyl piperazine-1-carboxylate (8.53 g, 45.8 mmol), copper(I) iodide (0.871 g, 4.57 mmol), K3PO4 (19.46 g, 91.68 mmol), 1,2-ethanediol (5.1 mL, 91 mmol) in isopropyl alcohol (80 mL) in a sealed tube was heated at 80° C. in an oil bath for 2 days. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed with saturated NaHCO3, dried (MgSO4) and concentrated. Purification by flash chromatography on silica gel (20% EtOAc/hexanes to 30% EtOAc/hexanes) afforded 5.75 g (37%) of desired product. MS calculated for C14H20BrN3O2: (M+H) 343; found 342.0, 344.0.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:26][CH3:25])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CN
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C=O)cc1OCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CNCc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Yield: 35.8 %

Procedure:
A mixture of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene-8-carbaldehyde (0.35, 0.90 mmol), methylamine (0.9 mL, 1.80 mmol, 2M solution in THF) and 4 Å molecular sieves in CHCl3 were stirred at RT for 1.5 h before sodium triacetoxyborohydride (0.57 g, 2.7 mmol) was added. The resultant mixture was stirred for 16 h then washed with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with 10% methanol in DCM and the combined organic phases dried (Na2SO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% methanol in DCM) to give [2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylmethyl]-methyl-amine (109 mg, 36%). LCMS: RT=1.90 min, [M+H]+=339
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[CH3:27][C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=3)=[CH:10][CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:23][CH:24]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cncc(C)c1
Reactant: Cc1csc(N)n1
Product: Cc1cncc(Nc2ccc(C)nc2C(=O)Nc2nc(C)cs2)c1

Procedure:
The title compound, was prepared from 6-Methyl-3-(5-methyl-pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methylthiazole in accordance with the general method of Example 78, step 2 to yield the final compound as a yellow solid, MS (ISP): m/e=340.3 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[NH:5][C:4]1=[O:9])[CH3:2].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH2:1]([CH:3]1[NH:7][C:6](=[O:8])[N:5]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:4]1=[O:9])[CH3:2]
Reactant: CCC1NC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Product: CCC1NC(=O)N(Cc2ccc(OC)cc2)C1=O

Procedure:
Using 5-ethylimidazolidine-2,4-dione (2.00 g) and 4-methoxybenzyl chloride (2.54 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (3.08 g) was obtained.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)[CH2:8][CH2:7]1>C(OCC)(=O)C>[Cl:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]2[S:16][C:15]([N:17]=[C:1]=[O:2])=[N:14][N:13]=2)[CH2:10][CH2:11]1
Reactant: Nc1nnc(C2CCC(Cl)CC2)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C=Nc1nnc(C2CCC(Cl)CC2)s1

Procedure:
A saturated solution of phosgene in ethyl acetate (500 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. 5-(4-Chlorocyclohexyl)-2-amino-1,3,4-thiadiazole (6 grams) is added to the reaction vessel and the resulting mixture is stirred and heated at reflux for a period of about 4 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-(4-chlorocyclohexyl)-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][N:37]2[CH:41]=[C:40](B(O)O)[CH:39]=[N:38]2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:40]3[CH:39]=[N:38][N:37]([CH2:36][CH2:35][N:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH:41]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OB(O)c1cnn(CCN2CCOCC2)c1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
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: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(CCN4CCOCC4)c3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (1-(2-morpholinoethyl)-1H-pyrazol-4-yl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and the mixture was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After reaction completion, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 3 the title compound (0.08 g, 66%). LCMS: 547.35 (M+1)+; HPLC % 97.60 (@254 nm) (Rt; 4.071; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.; 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.44 (s, 1H), 8.17 (s, 1H), 8.05 (t, 1H), 7.81 (s, 1H), 7.30 (s, 1H), 7.10 (s, 1H), 5.85 (s, 1H), 4.26 (d, 2H, J=4 Hz), 4.0 (d, 2H, J=6.4 Hz), 3.49-3.53 (m, 6H), 2.72 (t, 2H), 2.40 (bs, 6H), 2.20 (s, 3H), 2.17 (s, 3H), 2.10 (s, 3H), 1.6.1-1.70 (m, 4H), 1.42-1.50 (m, 4H).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([OH:14])=[N:10]2)=[CH:5][CH:4]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C.CS(C)=O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][C:11]([O:14][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccc(Br)cc2)n1
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Br)cc2)n1
Temperature: 0 °C
Yield: 48 %

Procedure:
A 3.9 g portion of sodium was dissolved in 50 ml of ethanol and was added to a solution of 41 g of 1-(4-bromophenyl)-3-hydroxy-1,2,4-1H-triazole in 150 ml of dimethylsulfoxide. The mixture was heated at 60° for 45 minutes, and then 30.9 g of ethyl 2-bromopropionate was added. The mixture was heated for 2 hours more, and was then cooled and poured over ice-water. The solid was collected and dried, and was recrystallized from toluene. The mother liquor was concentrated under vacuum, and the residue was recrystallized from ethanol. That product was combined with the first portion of product and recrystallized from ethanol to obtain 27.9 g of the desired product, m.p. 64°-66°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]([OH:18])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:40]([NH:48][NH2:49])(=[O:47])[C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][CH2:15][C:16](=[O:18])[NH:49][NH:48][C:40]([C:41]2[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=2)=[O:47])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NNC(=O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OCC(=O)NNC(=O)c2ccncc2)CC1
Reaction time: 18 h

Procedure:
A solution of 4-carboxymethoxypiperidine-1-carboxylic acid tert-butyl ester (Preparation 1, 1.25 g, 4.82 mmol), ethyl-(3-dimethylaminopropyl)carbodiimide (924 mg, 4.82 mmol) and N-hydroxybenzotriazole (651 mg, 4.82 mmol) in anhydrous CH2Cl2 (30 ml) were stirred at rt for 10 min. Isonicotinic acid hydrazide (601 mg, 4.38 mmol) was added in one portion and stirring continued for a further 18 h. The reaction mixture was diluted with CH2Cl2 (150 ml) and washed with water (30 ml), saturated aqueous NaHCO3 (30 ml) and brine (30 ml). After drying (MgSO4) the solvent was removed to afford the title compound: RT=2.89 min; m/z (ES+)=379.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:26])[F:25])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:28][C:29]1([C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(OC(F)(F)F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(OC(F)(F)F)c4)C3)CC2)cc1
Yield: 75.7 %

Procedure:
The title compound (D153) (120 mg) was prepared according to the experimental procedure described in Description 144 starting from 5-chloro-2-(3-(3-(trifluoromethoxy)phenoxy)azetidin-1-yl)nicotinic acid (D107) (110 mg, 0.282 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (64.43 mg, 0.282 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].O1CCCC1>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>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][C:14]([CH:12]=[O:13])=[CH:15][CH:16]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
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: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 108.8 %

Procedure:
A mixture of 4-bromobenzotrifluoride (10.0 g), 4-formylphenylboronic acid (7.33 g), tetrakis(triphenylphosphine)palladium(0) (308 mg), potassium carbonate (30.7 g), tetrahydrofuran (300 mL) and water (100 mL) was stirred at 85° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added to it, which was then extracted with ethyl acetate twice and the combined organic layers were washed with saturated brine. After adding anhydrous magnesium sulfate to the organic layers, the desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in n-hexane (60 mL) with heating and thereafter cooled to 0° C. The resulting precipitate was recovered by filtration to give the titled compound as a gray solid (12.1 g).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:12]([C:14]1[CH:19]=[C:18]([O:20]C)[N:17]=[C:16]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[CH:15]=1)=[O:13].Cl.N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C:12]([C:14]1[CH:15]=[C:16]([N:22]2[CH2:27][CH2:26][CH:25]([N:28]3[C:36]4[C:31](=[N:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:37])[CH2:24][CH2:23]2)[NH:17][C:18](=[O:20])[CH:19]=1)=[O:13]
Reactant: COc1cc(C(=O)N2CCc3c2ccc(F)c3F)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2c1ccc(F)c2F
Reaction time: 0.12 h

Procedure:
A well stirred mixture of 100 mg (0.197 mmol) 1-[4′-(4,5-difluoro-2,3-dihydro-indole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 0.500 g (4.33 mmol) pyridine hydrochloride was kept in a melt for 7 min using a hot air blower. After the reaction had cooled the mixture was dissolved in DMF and purified by preparative HPLC. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:20]=[C:19]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: Brc1cccc(I)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
Product: Brc1cccc(-c2cccc3ccccc23)c1
Reaction time: 24 h
Yield: 76 %

Procedure:
Under an argon gas atmosphere, 200.0 g (1.163 mol) of 1-naphthalene boronic acid, 329.0 g (1.163 mol) of 3-bromoiodobenzene, 26.9 g (23.3 mmol) of tetrakis(triphenylphosphine)palladium(0), 3.7 L of toluene and 1.74 L of 2M sodium carbonate solution were mixed, and stirred for 24 hours while being refluxed. After the reaction in the mixture was over, the mixture experienced filtration, through which aqueous phase thereof was eliminated. After organic phase thereof was cleansed by water and dried with magnesium sulfate, toluene was distilled away under reduced pressure. Residue thereof was refined by silica-gel column chromatography, such that 250 g of 1-(3-bromophenyl)naphthalene was obtained with an yield of 76%.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:26])[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]4[C:23]=3[N:22]([CH:24]=2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:15]4=[O:25])[CH:2]=1.[CH:27](=O)C1C=CC=CC=1>>[CH2:7]([C:8]1[C:9](=[O:26])[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:21]=2[N:22]([CH:24]=1)[C:23]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[C:15]3=[O:25])[C:3]1[CH:2]=[CH:27][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccccc3c(=O)c3cccc1c32
Product: O=c1c(Cc2ccccc2)cn2c3ccccc3c(=O)c3cccc1c32
Yield: 72 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) obtained in Example 18<step 2>was reacted with benzaldehyde (0.13 mL) to obtain the title compound (194 mg; 72%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][CH2:10][CH2:11][CH2:12]Br.C(N(C(C)C)CC)(C)C>C(#N)C>[Br:9][CH2:10][CH2:11][CH2:12][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNc1ccccc1
Reactant: BrCCCBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCCBr)c1ccccc1
Yield: 37.7 %

Procedure:
N-methylaniline (1.01 mL, 9.33 mmol) was reacted with 1,3-dibromopropane (0.947 mL, 9.33 mmol) and diisopropylethylamine (2.55 mL, 18.66 mmol) in ACN at 70° C. for 12 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide the intermediate 9a as a yellow oil (0.80 g, 3.52 mmol, 37% yield). HRMS (ESI, positive) m/z calcd. for C10H15NBr [M+H]+: 228.03824, found: 228.03824. 1H NMR (CDCl3, 400 MHz) δ 7.67 (t, J=8.4 Hz, 2H), 6.71 (d, J=8.0 Hz, 2H), 6.617 (t, J=7.2 Hz, 1H), 3.562 (t, J=6.8 Hz, 2H), 3.431 (t, J=7.2 Hz, 2H), 2.878 (s, 3H), 2.072 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[C:10](O)[N:9]2[C:13]([CH3:16])=[N:14][N:15]=[C:8]2[N:7]=1)=[O:5])[CH3:2].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:10]1[N:9]2[C:13]([CH3:16])=[N:14][N:15]=[C:8]2[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(O)n2c(C)nnc2n1
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cc(Cl)n2c(C)nnc2n1
Temperature: 80 °C

Procedure:
To a suspension of the product obtained in Step 1 (4.3 g) in 50 ml of phosphorus oxychloride was dropwise added 2.6 g of N,N-dimethylaniline at room temperature. The mixture was heated at 80° C. for one hour, excess phosphorus oxychloride was removed by distillation under reduced pressure, and the remaining reddish brown oil was shaken with 300 ml dichloromethane and 300 ml of water. The pH was adjusted to 7 to 8 with saturated sodium bicarbonate solution, the dichloromethane layer was collected, and the aqueous layer was again extracted with 200 ml of fresh dichloromethane. The chloroform layers were joined together, washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The dried filtrate was concentrated under reduced pressure, and the oily product left was purified by silica gel chromatography, giving 4.2 g of the objective compound as faint yellow crystals.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]([Br:9])=[CH:7][N:8]=1.[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl.C(OCC)(=O)C>CN(C)C=O>[Br:3][C:4]1[N:5]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[C:6]([Br:9])=[CH:7][N:8]=1
Reactant: Brc1cnc(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(Br)cnc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.212 g, 5.30 mmol) was added in portions to a 0° C. solution of 2,5-dibromo-1H-imidazole (0.600 g, 2.67 mmol) in N,N-dimethylformamide (4 mL), and the resulting mixture stirred for 30 min at 0° C. A solution of 2-(trimethylsilyl)ethoxymethyl chloride (0.665 g, 4.01 mmol) in N,N-dimethylformamide (0.5 mL) was added at 0° C., and the resulting solution stirred for an additional 2.5 h at room temperature. The reaction mixture was poured into ethyl acetate (20 mL), washed with brine (3×5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, ethyl acetate/petroleum ether) to afford 2,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (0.390 g, 41%) as light yellow oil. MS (ESI, pos. ion) m/z 357, 355, 359 [M+H]+.