Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11]C#N)[CH:7]=[CH:8][C:9]=1[F:10].CO[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=1)=[O:17].Cl>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH2:11][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[O:17])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: COC(=O)c1cccc(C)n1
Reactant: N#CCc1ccc(F)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(C(=O)Cc2ccc(F)c(Cl)c2)n1

Procedure:
A dispersion of sodium hydride, (60% in mineral oil, 0.7 g, 17.7 mmol) is added to ethanol (25 mL). When gas evolution ceases, 3-chloro-4-fluorophenylacetonitrile (Fluorochemicals, 2.0 g, 11.8 mmol) and 6-methyl-pyridine-2-carboxylic acid methyl ester (1.8 g, 11.8 mmol), are added. The mixture is refluxed for 2.5 h and adjusted to pH 7 with 1 N hydrochloric acid. The mixture is concentrated in vacuo. Concentrated hydrochloric acid (50 mL) is added to the mixture after which it is refluxed for 1.5 h. The mixture is poured over ice and adjusted to pH 8 with 5 N sodium hydroxide. The mixture is extracted with methylene chloride and the organic portions dried over anhydrous sodium sulfate. The mixture is filtered and concentrated in vacuo to yield the title compound, 2.1 g (68%), as a yellowish solid.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([C:25]4[C:26]5[N:27]([CH:44]=[CH:45][N:46]=5)[CH:28]=[C:29]([Sn](CCCC)(CCCC)CCCC)[N:30]=4)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:2]1.[C:47]([O:51][C:52]([N:54]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:55]1[C:60]([Cl:61])=[N:59][CH:58]=[C:57](Br)[N:56]=1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>O1CCOCC1.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>[C:47]([O:51][C:52]([N:54]([C:55]1[C:60]([Cl:61])=[N:59][CH:58]=[C:57]([C:29]2[N:30]=[C:25]([N:17]([C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[C:14]3[CH:15]=[CH:16][C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:3]5[CH2:2][O:1][CH2:4]5)[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)[C:26]3[N:27]([CH:44]=[CH:45][N:46]=3)[CH:28]=2)[N:56]=1)[C:63](=[O:64])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2ccnc2c(N(C(=O)OC(C)(C)C)c2ccc(N3CCN(C4COC4)CC3)cc2)n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)cnc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)cc3)n2)cnc1Cl

Procedure:
tert-Butyl 4-(4-(Oxetan-3-yl)piperazin-1-yl)phenyl(6-(tributylstannyl)imidazo[1,2-a]pyrazin-8-yl)carbamate V (1000 mg, 1.4 mmol), 2-Bis(tert-butoxycarbonyl)amino-6-bromo-3-chloropyrazine XI (552 mg, 1.35 mmol), and PdCl2(PPh3)2 (142.77 mg, 0.20 mmol), in 1,4-Dioxane (11.27 ml) was irridated in the microwave for 20 min at 140° C. The reaction was absorbed onto celite and eluted off a 40 g Gold Isco column using 0-10-100% (30% MeOH/DCM) over 20 column volumes. Fractions 34-39 were collected and concentrated. According to NMR, the title compound XII was identified and isolated.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:16][CH2:17][CH3:18])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[N:13][NH:14][CH:15]=2)=[N:9][CH:10]=1)[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[CH2:17]([O:16][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[N:14][N:13]([CH3:19])[N:12]=2)=[N:9][CH:10]=1)[CH3:18]
Reactant: O=C([O-])[O-]
Reactant: CCOC(OCC)c1ccc(-c2c[nH]nn2)nc1
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCOC(OCC)c1ccc(-c2cnn(C)n2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.3 %

Procedure:
In acetonitrile (25 mL) was dissolved 5-(diethoxymethyl)-2-(1H-1,2,3-triazol-4-yl) pyridine (1.34 g, 5.40 mmol) obtained in Step 4. To the solution were added potassium carbonate (2.24 g, 5.40 mmol) and iodomethane (0.405 mL, 6.48 mmol) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and water was added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 5-(diethoxymethyl)-2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (698 mg, 49% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:28])[CH3:27])=[CH:20][CH:19]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]([OH:29])[CH2:25][N:26]([CH3:27])[CH3:28])=[CH:20][CH:19]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cc1
Product: CN(C)CC(O)c1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)cc1
Yield: 69.5 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(2-(dimethylamino)-1-hydroxyethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (48 mg, 0.165 mmol) to afford the desired product (41 mg, 69%) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.38 (s, 1H), 8.22 (dd, J=8.8, 2.0 Hz, 1H), 8.07-7.98 (m, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.38 (s, 2H), 5.18 (dd, J=9.8, 4.3 Hz, 1H), 3.25-3.14 (m, 2H), 3.02 (s, 3H), 2.95 (s, 3H), 2.86-2.79 (m, 1H), 1.22-1.11 (m, 4H); ESI MS m/z 536 [C29H27Cl2N3O3+H]+; HPLC 95.1% (AUC), tR=11.42 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.[OH-].[Na+].Br[C@H:11]([CH3:15])[C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:4]1[N:3]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:2]=[N:1][CH:6]=[CH:5]1
Reactant: C[C@@H](Br)C(=O)O
Reactant: O=c1ccnc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)n1cnccc1=O
Temperature: 85 °C

Procedure:
To pyrimidin-4(3H)-one (0.908 g, 9.45 mmol) was added 5 N sodium hydroxide solution (3.8 mL) followed by (2R)-2-bromopropanoic acid (0.95 mL, 11 mmol). The reaction mixture was heated at 85° C. for 1 h. After cooled down to ambient temperature, it was neutralized with 2 M hydrochloric acid (5.2 mL) and then directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). Removal of the volatiles in vacuo afforded the title compound as a white solid. 1H NMR (DMSO-d6): δ 8.48 (d, J=2.7 Hz, 1H), 7.88 (dd, J=7.8, 2.8 Hz, 1H), 6.12 (d, J=7.6 Hz, 1H), 5.04 (q, J=7.3 Hz, 1H), 1.64 (d, J=7.5 Hz, 3H). LC/MS 169.1 (M+1).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].CS(O[CH2:21][CH:22]1[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]1)(=O)=O>CN(C=O)C>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][CH:22]2[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24][CH2:23]2)[C:6]1=[O:15]
Reactant: CC1(C)OCC(COS(C)(=O)=O)CO1
Reactant: NC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCC(CN2C(=O)C(N)Cc3ccccc32)CO1
Temperature: 60 °C
Yield: 57.1 %

Procedure:
Sodium hydride (60% in oil, 1.60 g, 39.80 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (3.59 g, 18.09 mmol), in anhydrous DMF (50 mL) at 0° C. over a period of 10 min. The reaction was stirred for a further 30 min before addition of (2,2-dimethyl-1,3-dioxan-5-yl)methyl methanesulfonate [CAS registary number 131372-64-0] (4.05 g, 18.09 mmol) and the reaction has then heated to 60° C. for a period of 16 h. The reaction was then cooled and evaporated before addition of sat. aqueous NaHCO3 (200 mL) and EtOAc (500 mL). The organic layer was then dried (MgSO4), filtered and evaporated and the residue was purified by column chromatography (MeOH:DCM, 3:37) to afford the title compound (3.00 g, 57%) as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]=O.O.[OH:10][CH2:11][CH2:12][O:13][NH:14][C:15]([C:17]1[C:18]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Cl:35])=[C:19]([Cl:26])[C:20]2[N:21]([CH:23]=[CH:24][N:25]=2)[CH:22]=1)=[O:16]>CC#N.CCOC(C)=O.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[OH:10][CH2:11][CH2:12][O:13][NH:14][C:15]([C:17]1[C:18]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][C:29]=2[Cl:35])=[C:19]([Cl:26])[C:20]2[N:21]([C:23]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:24][N:25]=2)[CH:22]=1)=[O:16]
Reactant: C1CCNCC1
Reactant: C=O
Reactant: O=C(NOCCO)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=C(NOCCO)c1cn2c(CN3CCCCC3)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Reaction time: 16 h
Yield: 48.9 %

Procedure:
Compound 39 was prepared by a modification of the procedure of T. Kercher et al. (manuscript in preparation). Piperidine (4 μL, 0.043 mmol) and 37% aqueous formaldehyde (5 μL, 0.065 mmol) were dissolved in 6:1 MeCN:water (0.5 ml), and stirred 30 minutes. 7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylic acid (2-hydroxyethoxy)amide (33a) (10 mg, 0.022 mmol) was added followed by scandium triflate (1 mg, 0.002 mmol). After stirring 16 hours, additional scandium triflate (1 mg), piperidine (3.8 μL) and aqueous formaldehyde (3.8 μL) were added. After about 60 hours, the reaction mixture was diluted with EtOAc and washed with water, 10% K2CO3, and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by flash column chromatography using the Biotage system (40:1 CH2Cl2/MeOH to 20:1 CH2Cl2:MeOH to 9:1 CH2Cl2/MeOH) provided the desired product (39) as a white solid (6 mg, 50%). MS APCI (+) m/z 556, 558, 560 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CD3OD) δ 8.83 (s, 1H), 7.56 (s, 1H), 7.54 (s, 1H), 7.27 (dd, 1H), 6.56 (d, 1H), 3.91 (m, 4H), 3.70 (m, 2H), 2.51 (broad s, 4H), 1.60 (broad s, 4H), 1.50 (broad s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][CH2:19][C:20]2[C:25](F)=[CH:24][CH:23]=[C:22](F)[C:21]=2[F:28])=[CH:4][CH:3]=1.ClC1C=CC=C(F)C=1C#CC1N(C2C=CC(F)=CC=2)C(C(OCC)=O)=CN=1>[Pd].C(OCC)(=O)C.C(O)C>[F:28][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][CH2:18][C:9]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(CCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Pd]
Agent: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(CCc2ccccc2F)n1-c1ccc(F)cc1

Procedure:
Ethyl 2-(2-fluorophenethyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (44) was prepared in a similar manner as that described for the synthesis of compound 18 using ethyl 2-((2-chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (42) (236 mg, 0.61 mmol), Pd/C (10% Degussa type, 23 mg), and ethyl acetate/ethanol (1:2) (61 mL).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[N:18]=[C:19]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:31][NH2:32]>C1COCC1.O.C(O)(=O)C>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[NH:18][C:19]1[C:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]=2[NH:32][N:31]=1
Reactant: O=C1CCc2sccc21
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: NN
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: Clc1cccc(Nc2n[nH]c3c2Cc2sccc2-3)c1Cl
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 2,3-Dichloro-1-isothiocyanato-benzene (1.2 g, 7.4 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (2,3-Dichloro-phenyl)-(4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-amine as brown solid in 30% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[K+].CS(C)=O.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>C(OCC)C.O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:14][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: BrCCCCCCBr
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: c1ccc(-c2ccccc2OCCCCCCOc2ccccc2-c2ccccc2)cc1
Temperature: 35 °C

Procedure:
A 250 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, a nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with o-phenylphenol (6.81 grams, 0.04 moles), with KOH pellets (2.64 grams, 0.04 moles, 85%), and with 50 mL of DMSO. The mixture was stirred at about 35° C. for about 1½ hours, then 1,6-dibromohexane (4.88 grams, 0.02 moles) was added in one portion. The reaction mixture was stirred at about 75° C. for about 2 hours, then it was poured into about 500 mL of water. A milky white suspension formed. The mixture was slurried with about 100 mL of diethyl ether, then it was transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with 5×100 mL of diethyl ether. The ether layers were combined, and were washed with 1×100 mL of water and with 1×100 mL of saturated aqueous sodium chloride. After drying the ether solution over anhydrous magnesium sulfate, the solution was filtered, and the solvent was removed by rotary evaporation at a bath temperature of about 60° C./P=3.4 kPa. The yield of product was 7.06 grams (84%) as a white solid having mp=92-95° C. Structure was confirmed by IR, GC/MS, and 1H- and 13C-NMR analyses.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(OC)cc1N
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3.1 mL of triethylamine and 1.3 mL of benzoyl chloride were added to 19 mL of methylene chloride solution containing 1.9 g of methyl 2-amino-4-methoxybenzoate while ice-cooled sequentially and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure and chloroform and 1.0 mol/L hydrochloric acid were added to the obtained residue. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 2.6 g of methyl 2-(benzamido)-4-methoxybenzoate as white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][N:13]([C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([N:13]([CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[CH:26][CH:25]=2)[N:3]=1
Reactant: Clc1cc2ccccc2cn1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc3ccccc3cn2)cc1
Yield: 17.9 %

Procedure:
3-Chloroisoquinoline (33 mg, 0.2 mmol) and tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (66 mg, 0.2 mmol) were reacted using general procedure A to afford tert-butyl (4-(isoquinolin-3-yl)phenyl)(methyl)carbamate as a clear oil (12 mg, 18%). 1H NMR (400 MHz, CDCl3): δ 9.33 (s, 1H), 8.09 (m, 2H), 8.05 (s, 1H), 7.99 (m, 1H), 7.87 (m, 1H), 7.69 (m, 1H), 7.58 (m, 1H), 7.38 (m, 2H), 3.32 (s, 3H), 1.48 (s, 9H); MS (ESI): 335 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:43])[CH:35]=[CH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:34](=[O:43])/[CH:35]=[CH:36]/[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)/C=C/c3ccccc3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 30 mg, 0.074 mmol) and triethylamine (70 mg, 0.69 mmol) in dichloromethane (6 ml) was added cinnamoyl chloride (18 mg, 148 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain title compound. 1H NMR (CDCl3, 300 MHz): δ 9.921 (s, 1H), 8.204-8.257(d, 1H ,J=15.9 Hz), 8.071-8.123 (d, 1H,J=15.6 Hz), 7.983-8.013 (d, 1H J=9 Hz), 7.806-7.834 (d, 2H, J=8.4 Hz), 7.63-7.68 (m, 3H), 7.569-7.597 (d, 2H,J=8.4 Hz), 7.396-7.412 (m, 3H), 7.059-7.066 (d, 1H, J=2.1 Hz), 1.858 (s, 6H); MS: m/z 539 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(C)=O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:12][C:9]2[CH:10]=[CH:11][C:2]([O:1][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(OS(=O)(=O)c2ccc(C)cc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl 2,5-dihydroxybenzoate (10 g, 59.5 mmol), potassium carbonate (50.0 g, 362 mmol), and dry acetone (450 ml) was stirred at room temperature for 30 min. 4-Methylbenzenesulfonyl chloride (11.44 g, 60.0 mmol) was added portionwise and the mixture was refluxed for 7 h. (Bromomethyl)benzene (25.4 g, 149 mmol) was added and the resulting mixture was refluxed overnight. After cooling, the precipitate was filtered, and the filtrate was evaporated. The residue was loaded onto a silica gel column and was eluted with hexane/ethyl acetate=4:1 to yield the title compound as a yellow solid. 22 g.
Reaction SMILES: C(C1N(CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)[C:9](=[O:29])C(CC(N2CCSCC2)=O)=C(C)N=1)CCC.[CH2:40]([C:44]1[N:49]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[C:63]3[NH:67][N:66]=[N:65][N:64]=3)=[CH:53][CH:52]=2)[C:48](=[O:68])[C:47]([CH2:69][C:70]([N:72]2[CH2:77][CH2:76]N(C)[CH2:74][CH2:73]2)=[O:71])=[C:46]([CH3:79])[N:45]=1)[CH2:41][CH2:42][CH3:43].[CH2:80](C1N(CC2C=CC(C3C=CC=CC=3C3NN=NN=3)=CC=2)C(=O)C(CC(N2CCN(C(=O)C)CC2)=O)=C(C)N=1)CCC>>[CH2:40]([C:44]1[N:49]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=3[C:63]3[NH:64][N:65]=[N:66][N:67]=3)=[CH:53][CH:52]=2)[C:48](=[O:68])[C:47]([CH2:69][C:70]([N:72]2[CH:77]([CH3:76])[CH2:9][O:29][CH2:74][CH:73]2[CH3:80])=[O:71])=[C:46]([CH3:79])[N:45]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nc(C)c(CC(=O)N2CCN(C)CC2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCCCc1nc(C)c(CC(=O)N2CCSCC2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: CCCCc1nc(C)c(CC(=O)N2CCN(C(C)=O)CC2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCCCc1nc(C)c(CC(=O)N2C(C)COCC2C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
2-n-butyl-5-thiomorpholinocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4-(3H)-one (Compound 75) 2-n-butyl-5-(4'-methylpiperazinocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4-(3H)-one (Compound 76) 2-n-butyl-5-(4'-acetylpiperazinocarbonylmethyl)-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-pyrimidin-4-(3H)-one (Compound 77)
Reaction SMILES: C(=[C:8]1[C:17]2[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.CO.[O:21]=[O+][O-]>ClCCl>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:21])[C:17]=2[N:16]=1
Reactant: Cc1ccc2c(n1)C(=Cc1ccccc1)CCC2
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc2c(n1)C(=O)CCC2

Procedure:
Intermediate 200A2 in dichloromethane (100 mL)/methanol (200 mL) was cooled to −78° C. Ozone was passed through the mixture for 1-2 h until the mixture had a light blue color. The reaction mixture was purged with nitrogen followed by the addition of dimethyl sulfide (10 mL). The mixture was stirred for 30 m and evaporated. The residue was partitioned between ether and 1M HCl. The organic layer was extracted with 1N HCl (2×) and the acidic, aqueous layers were pooled, washed with ether (3×), cooled with crushed ice, and carefully basified with solid NaOH. The basic layer was extracted with chloroform, freed of solvent, and the residue was passed through a column of SiO2 with 80% ethyl acetate/hexane to give impure Intermediate 200A3 as a yellow solid. Further purification of this mixture was conducted by oxidation of the minor product: (˜3%) 8-oxo-5,6,7,8-tetrahydro-quinoline-2-carbaldehyde in formic acid (15 mL) at 0° C. by dropwise addition of H2O2 (2.1 mL, 30% solution). The mixture was stirred for 1.5 h, quenched with crushed ice, diluted with chloroform, and basified with 2 M NaOH to pH>8. The chloroform layer was dried, filtered and evaporated to give pure 2-methyl-6,7-dihydro-5H-quinolin-8-one (Intermediate 200A3), 15.1 g (50% over two steps).