Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15][CH:16]=[CH2:17])=[CH:4][CH:3]=1.I[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CN(C=O)C.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>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[CH2:15]/[CH:16]=[CH:17]/[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1-[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol (0.152 g, 0.49 mmol), iodobenzene (0.06 mL, 0.49 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.05 mmol), and triethylamine (0.68 mL, 4.9 mmol) were combined in DMF (4 mL) and the mixture was purged with N2 (g) for 5 minutes. The reaction was then sealed and stirred at 100° C. overnight. After aqueous workup, the crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:13]([Cl:34])=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:19][CH:18]=[CH:17][CH:16]=2>>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([Cl:34])[C:12]=2[N:11]=[CH:1]1)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)c(Cl)nc2ccccc12
Reactant: CCOC(OCC)OCC
Product: CC(C)(C)OC(=O)NCCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
0.36 ml (2.14 mmol) of triethyl ortho-formate was added to 0.15 g (0.428 mmol) of 3-amino-4-[3-(tert-butoxycarbonylamino)-propylamino]-2-chloro-quinoline. The mixture was stirred at 100° C. for 2 hours and then at 80° C. for overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol 150:1 to 100:1 (v/v)) to obtain 0.14 g (0.388 mmol) of 1-[3-(tert-butoxycarbonylamino)propyl]-4-chloro-1H-imidazo[4,5-c]quinoline shown below as white powder (mp: 155-156° C.). ##STR36## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3380, 1680, 1520.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:25]3[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[C:27]([O:28][CH3:29])[CH:26]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccnc21
Reactant: COc1ccc(B(O)O)cc1OC
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: C1CCOC1
Product: COc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc1OC
Temperature: 120 °C

Procedure:
1-Benzenesulfonyl-3-bromo-1H-pyrrolo[2,3-b]pyridine (4, 1.00 g, 2.96 mmol) was dissolved in tetrahydrofuran (16 mL) and 3,4-dimethoxyphenyl boronic acid (1.35 g, 7.41 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.1 mmol), and 1 M potassium carbonate (8 mL) were added. The reaction mixture was heated in a CEM Discover microwave at 120° C. for 10 minutes. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and water. The organic portions were dried with anhydrous magnesium sulfate, filtered, and the filtrate was adsorbed onto silica. The mixture was purified by flash chromatography (30% ethyl acetate:hexanes) to provide the desired product, 5, (909 mg, 78%). MS(ESI) [M+H+]+=394.9.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[F:28][C:29]([F:35])([F:34])[CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C:29]([F:35])([F:34])[F:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: O=C(O)CC(F)(F)F
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(CC(F)(F)F)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (11 mg, 35%), MS (ISP) m/z=442.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and 3,3,3-trifluoropropanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1.Cl.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH2:24][C:25]([OH:27])=[O:26])[C:11]3[C:12]([N:23]=2)=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:16]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2CC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.4 %

Procedure:
To tert-butyl [2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]acetate (209 mg) was added a solution of 4 N hydrogen chloride in ethyl acetate (8.0 ml), and the mixture was stirred at room temperature for 5 hours to hydrolyze. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over MgSO4, and the solvent was distilled off under reduced pressure. The resulting crystals were collected by filtration to obtain [2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]acetic acid (129 mg, 43%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9][CH:10]=1)=[O:17])(=[O:30])=[O:31]
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: Cc1nc(-c2ccc(F)cc2)ncc1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3ccc(F)cc3)nc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A mixture of 2-(4-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid (232 mg, 1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg 1 mmol) in dry DMF (12 mL) is treated with diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. A solution of 3-methylsulfamoylbenzylamine (300 mg, 1.5 mmol) in dry DMF (1.5 mL) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue is partitioned between EtOAc and water. The organic phase is separated, washed with saturated NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 60% EtOAc in heptane to afford 2-(4-fluorophenyl)-4-methylpyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (210 mg, 52%) as a solid. MS: 415 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.42 (s, 3H), 2.63 (s, 3H), 4.60 (d, 2H), 7.37-7.40 (t, 2H), 7.50 (s, 1H), 7.60-7.75 (m, 3H), 7.80 (s, 1H), 8.45-8.50 (dd, 2H), 8.88 (s, 1H), 9.30 (t, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:12]#[C:13][C:14]([OH:17])([CH3:16])[CH3:15]>C(N)(C)C.CO.[Cu]Cl>[OH:17][C:14]([CH3:16])([CH3:15])[C:13]#[C:12][C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1
Reactant: C#Cc1cccc(OC)c1
Reactant: CC(C)(O)C#CBr
Agent: Cl[Cu]
Solvent: CO
Solvent: CC(C)N
Product: COc1cccc(C#CC#CC(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
50 mg of copper (I) chloride were dissolved in a mixture of 10 ml of isopropylamine and 15 ml of methanol in an atmosphere of argon, and 660 mg of 3-ethynylanisole were then added to the reaction mixture, followed by stirring at room temperature for 10 minutes. 1300 mg of 1-bromo-3-hydroxy-3-methyl-1-butyne were then dropwisely added to the solution over a time of about 2 hours, followed by stirring at room temperature for 2 hours. The solvent was then evaporated from the reaction mixture, and the residue was then neutralized and diluted by 1N hydrochloric acid, and subjected to extraction with dichloromethane three times. The organic layer was then dried over magnesium sulfate, and the solvent was then evaporated. The residue was then purified by silica-gel column chromatography using benzene as an eluent to obtain 800 mg of 5-hydroxy-5-methyl-1-(3-methoxyphenyl)hexane-1,3-diyne.
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.[NH2:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])([CH3:28])[C:19]2=[O:36])=[C:15]([O:39][CH3:40])[CH:14]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([CH2:17][C:16]1[CH:37]=[CH:38][C:13]([N:12]3[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:14][C:15]=1[O:39][CH3:40])[C:19](=[O:36])[C:20]2([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH3:28]
Reactant: COc1cc(N)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: BrCCCCBr
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc(N2CCCC2)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 115 °C

Procedure:
0.4 g of sodium bicarbonate powder and 0.14 ml of 1,4-dibromobutane are added to 0.5 g of the compound of Example 48 in 50 ml of hexamethyl-phosphoramide. The reaction mixture is heated at 115° C. for 10 hours. The reaction mixture is hydrolysed at room temperature and extracted with ethyl acetate. The organic phase is washed several times with water and dried over anhydrous sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 95/5 (v/v) cyclohexane/ethyl acetate mixture. The oil obtained is treated with hydrochloric acid in diethyl ether; M.p.=198° C. (HCl.0.4H2O).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]([NH2:18])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2.[CH3:19][N:20]([CH:22](OC)OC)[CH3:21]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16](/[N:18]=[CH:19]/[N:20]([CH3:22])[CH3:21])=[O:17])[N:11]=1)[CH2:7][CH2:6][O:5]2
Reactant: NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)/C=N/C(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 100 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 12-bromo-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (100 mg, 0.380 mmol) in 1,4-dioxane (3 mL) was added DMF-DMA (147 mg, 1.14 mmol). The resulting mixture was stirred at 100° C. for 1 h under nitrogen atmosphere. After removal of the solvent, the residue was washed with ether to afford 12-bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-4-carboxamide (80 mg, 68% yield), which was used in the next step without further purification. LCMS (ESI) m/z: 363.3 [M+H+].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[CH:19][C:18]=1[C:31](=[O:34])[CH2:32][Br:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[CH2:9]([O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:20]([Br:1])=[CH:19][C:18]=1[C:31](=[O:34])[CH2:32][Br:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C(CBr)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 18 h

Procedure:
N-bromo succinimide (2.67 g, 0.015 mol) was added to a stirred solution of crude 1-(2,4-Bis-benzyloxyphenyl)-2-bromo-ethanone (ca. 6.16 g, 0.015 mol) in dimethylformamide (50 ml) and the mixture was stirred for 18 h. The mixture was concentrated to dryness, dissolved in dichloromethane (50 mL) and washed with (2×50 ml). The combined organic phases were dried over magnesium sulphate and concentrated to give 1-(2,4-Bis-benzyloxy-5-bromo-phenyl)-2-bromo-ethanone as a white solid, which was used without further purification.
Reaction SMILES: O[C:2]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:2]2[C:6]3[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:22])[CH3:21])=[CH:29][CH:28]=1)([CH3:32])[CH3:31]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)Cc1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2Cc1ccc(C(C)C)cc1
Yield: 63 %

Procedure:
Using N-(3-hydroxy-3-(4-isopropylbenzyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 250, the title compound was synthesized in the same manner as in Example 271. Yield: 63%. Melting point: 130-132° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]1([CH:7]2[C:11]3[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.CCCCCC>[OH:19][CH2:8][CH:7]([C:11]1[C:12]([CH3:18])=[CH:13][C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=1[OH:9])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc(C)c2c(c1C)OC(=O)C2c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(C(CO)c2ccccc2)c(O)c1C
Yield: 82 %

Procedure:
Using 3-phenyl-4,6,7-trimethyl-1-benzofuran-2 (3H)-one obtained in Reference Example 228, the title compound was synthesized in the same manner as in Reference Example 8. Yield 82%. Melting point: 103-104° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22](O)=[O:23])[CH:13]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C=O>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([O:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:23])[CH:13]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 1-adamantanol (152 mg, 1.0 mmol), 3-quinolinecarboxylic acid (173 mg, 1.0 mmol), and dimethylaminopyridine (122 mg, 1.0 mmol) in dichloromethane (2 mL) and N,N-dimethylformamide (2 mL) was cooled to 0° C. 1,3-Dicyclohexylcarbodiimide (227 mg, 1.1 mmol) in dichloromethane (1 mL) was added in one portion. The reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then diluted with dichloromethane (40 mL) and washed with 1 M sodium hydroxide (3×30 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through Celite, and rotary evaporated. The resulting material was purified by spinning thin-layer chromatography (3% methanol in chloroform). The purest fraction was rotary evaporated, and the resulting material was recrystallized from ethanol. This provided 42 mg (14%) of (101):
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:8]=2[CH2:7][O:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>>[Cl:14][C:13]1[C:8]2[CH2:7][O:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Clc1cccc2c1COc1ccccc1C2=CBr
Product: O=[N+]([O-])c1cccc(C=C2c3ccccc3OCc3c(Cl)cccc32)c1

Procedure:
Following procedures essentially as described in Example 230, 11-bromomethylene-7-chloro-6,11-dihydro-dibenzo[b,e]oxepine is combined with m-nitrophenyl boronic acid to provide the title compound. The pure Z isomer is isolated by crystallization (diethyl ether) to give 1.4 g (31.7% yield) product. 1H NMR (400 MHz, CDCl3) δ 8.038-8.017 (d, 1H), 7.976 (s, 1H), 7.511-7.491 (d, 1H), 7.431-7.410 (d, 1H), 7.369-7.253 (m, 3H), 7.160-7.121 (t, 1H), 7.041-7.005 (m, 2H), 6.928-6.919 (d, 1H), 6.908-6.898 (d, 1H), 5.60 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:18][S:19]([O:9][CH2:8][CH:6]1[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]1)(=[O:21])=[O:20]
Reactant: CC1(C)CC(CO)CCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CC(COS(C)(=O)=O)CCO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2,2-Dimethyltetrahydro-2H-pyran-4-yl)methanol (2.54 g) was dissolved in dry DCM (40 mL) and triethylamine (4.9 mL) was added with stirring. The solution was cooled (ice bath) under nitrogen and methanesulphonyl chloride (1.77 mL) was added dropwise over 5 mins. The mixture was allowed to warm slowly to room temperature as the ice bath melted and was left for 16 h. The mixture was shaken with saturated sodium bicarbonate solution and the aqueous layer was extracted with DCM (×2). The combined organics were washed with brine, dried using a hydrophobic frit and evaporated to give the title compound (3.93 g).
Reaction SMILES: ClC(Cl)(Cl)C[CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([OH:17])(=[O:16])[CH:15]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Product: O=C(O)C=Cc1ccccc1
Yield: 76.3 %

Procedure:
A mixture of 129 g of 1,1,1,3-tetrachloro-3-phenylpropane, 74 g of glacial acetic acid and 39 g of Wolfatit OK 80 cation exchanger is heated to 118° to 124° C. for 15 h. The cation exchanger is removed from the hot reaction mixture by filtration. After cooling the mixture, filtration of the crystals and their washing with water, 56.5 g of cinnamic acid is obtained. Condensation of the filtrate followed by filtration of the crystals gives another 9.5 g of cinnamic acid with total yield of 89% (melting point after recrystallization 128° to 135° C., min. 98% purity).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[CH:9]([CH3:11])[CH3:10].[NH2:14][C:15]([CH3:36])([CH3:35])[CH2:16][N:17]1[C:29]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:22]=[C:21]([NH2:30])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34]>ClCCl>[NH2:30][C:21]1[C:20]2[N:19]=[C:18]([CH2:31][O:32][CH2:33][CH3:34])[N:17]([CH2:16][C:15]([NH:14][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])([CH3:35])[CH3:36])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CC(C)(C)NC(=O)C(C)C
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Triethylamine (556 μL, 4.00 mmol) and isobutyryl chloride (230 μL, 2.20 mmol) were added sequentially to a chilled (0° C.) solution of 1-(2-amino-2-methylpropyl)-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (628 mg, 2.00 mmol) in dichloromethane (20 mL). The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was quenched with aqueous saturated sodium bicarbonate and diluted with dichloromethane (50 mL). The organic layer was separated, washed sequentially with water and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure to an amber foam. This material was dissolved in hot propyl acetate (10 mL) and then allowed to cool overnight. Hexanes were added and the now cloudy solution was heated until clear and then allowed stand until crystals formed. The solvent was removed by pipette. The crystals were rinsed with cold propyl acetate/hexanes and then dried under high vacuum at 70° C. to provide 464 mg of N-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-1,1-dimethylethyl]-2-methylpropionamide as an off white crystalline solid, mp 154.5-155.5° C. Anal. calcd for C20H28N6O2: % C, 62.48; % H, 7.34; % N, 21.86. Found: % C, 62.14; % H, 7.62; % N, 21.71.
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:34])([CH3:33])[C@:27]([C:36]3[CH:41]=[C:40](Br)[CH:39]=[CH:38][C:37]=3[F:43])([CH3:35])[N:26]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:44][C:45]1[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=1[C:53]([F:56])([F:55])[F:54]>>[NH2:24][C:25]1[N:30]([CH3:31])[C:29](=[O:32])[C:28]([CH3:33])([CH3:34])[C@:27]([C:36]2[CH:41]=[C:40]([NH:44][C:45]3[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][C:46]=3[C:53]([F:54])([F:55])[F:56])[CH:39]=[CH:38][C:37]=2[F:43])([CH3:35])[N:26]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(C)(C)C(=O)N2C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(C#N)cc3C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of (S)-2-{[bis-(4-methoxy-phenyl)-phenyl-methyl]-amino}-6-(5-bromo-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate K) and 4-amino-3-trifluoromethyl-benzonitrile according to procedure B followed by deprotection yielded the title compound as a pale yellow solid. MS (ESI): m/z=448.2 [M+H]+.