Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Li+].C(OP([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(OCC)=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1(/[CH:21]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a stirred mixture of lithium tert-butoxide (124.6 g, 1.56 mol, 1.10 equiv) in DCM (2000 mL) under N2 at RT was added ethyl 2-(diethoxyphosphoryl)acetate (317 g, 1.41 mol, 1.00 equiv). Benzaldehyde (150 g, 1.41 mol, 1.0 equiv) was then added dropwise to the stirred reaction, and the resulting reaction mixture was stirred under N2 at 25° C. overnight. The reaction mixture was diluted with DCM (2 L). The organic layer was washed with water (3×2 L) and brine (1×2 L), dried (Na2SO4), filtered, and evaporated in vacuo. The crude residue was purified by SiO2 chromatograph eluting with EtOAc/petroleum ether (3.3 to 1% EtOAc) to afford 180 g (72%) of ethyl (2E)-3-phenylprop-2-enoate (31) as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[O:11][C:10]([C:12]3[C:15](Cl)(Cl)[C:14](=[O:18])[CH:13]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[O:11][C:10]([C:12]3[CH2:15][C:14](=[O:18])[CH:13]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(c2ccc(Oc3ccc(F)cc3)o2)C1(Cl)Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1C=C(c2ccc(Oc3ccc(F)cc3)o2)C1
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a stirred suspension of 3-[5-(4-fluorophenoxy)-2-furyl]-4,4-dichloro-2-cyclobutenone (6.4 g; 20 mM) in acetic acid (25 ml) was added zinc dust (6.5 g; 100 mM) at room temperature. After stirring for 2 hr, zinc was filtered off. The filtrate was evaporated in vacuo. The residue was purified by flash column (SiO2) eluting with ethyl acetate-n-hexane (1:7) to give 2.2 g (yield 45%) of subtitle compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([Cl:27])[C:25]=1[Cl:26])[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([Cl:27])[C:25]=1[Cl:26])[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1
Product: FC(F)(F)c1cc(Nc2cc(Cl)c(Cl)c(Cl)c2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 3,4,5-trichloroaniline (56 mg, 0.288 mmol) similar to Example 180 and was isolated as a white solid (30 mg, 37%). 1H NMR (CDCl3): 9.58 (d, J=1.5 Hz, 1H), 8.99 (ddd, J=8.4, 4.9, 1.5 Hz, 1H), 8.79 (dd, J=5.4, 1.5 Hz, 1H), 7.99 (s, 1H), 7.76 (dd, J=7.8, 5.1 Hz, 1H), 7.40 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([C:13]3[O:17][C:16]([N:18]4[CH2:23][CH2:22][CH2:21][CH:20]([CH3:24])[CH2:19]4)=[N:15][C:14]=3[C:25]([F:28])([F:27])[F:26])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[CH3:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[O:17][C:13]([C:11]([NH:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[N:2]=[CH:3]4)=[O:12])=[C:14]([C:25]([F:28])([F:27])[F:26])[N:15]=2)[CH2:19]1
Reactant: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ncc4c3)o2)C1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4c(cnn4C(=O)Nc4ccccc4)c3)o2)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
To a solution of compound 49 (0.060 g, 0.152 mmol) in anhydrous methylene chloride (1.52 mL) at room temperature under argon was added phenyl isocyanate (0.018 mL, 0.160 mmol). The reaction mixture was stirred at room temperature for 17 h and another portion of phenyl isocyanate (0.018 mL, 0.160 mmol) was added. After additional stirring at room temperature for 17 h, the reaction mixture was quenched with methanol (1.0 mL) and concentrated. Purification by silica gel chromatography (eluant: 100% methylene chloride to 100% EtOAc gradient) gave 32.7 mg (42% yield) of 5-[[2-(3-methyl-1-piperidinyl)-4-(trifluoromethyl)-5-oxazolyl]carbonylamino]-N-phenyl-1H-indazole-1-carboxamide (50) as a white solid. 1H NMR (500 MHz, CD3OD) δ 8.31 (br d, 1H, J=8.8 Hz), 8.24 (m, 2H), 7.70 (m, 3H), 7.39 (br t, 2H, J=7.9 Hz), 7.16 (t, 1H, J=7.4 Hz), 4.90 (br s, 2H), 4.20 (m, 2H), 3.08 (td, 1H, J=12.4, 3.1 Hz), 2.75 (dd, 1H, J=12.3, 12.6 Hz), 1.89 (m, 1H), 1.82 (m, 1H), 1.74 (m, 1H), 1.65 (m, 1H), 1.23 (m, 1H), 1.01 (d, 3H, J=6.6 Hz). MS (M+1): 513.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])([O-])=O.[OH-:15].[Na+]>[Fe].[Zn].O.[O-2].[Zn+2].O>[CH2:11]([O:10][C:5]1[CH:6]=[C:7]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([O:15][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:6]=2)[CH:8]=[CH:9][C:4]=1[NH2:1])[CH:12]([CH3:14])[CH3:13]
Reactant: [OH-]
Reactant: CC(C)COc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Product: CC(C)COc1cc(-c2ccc(N)c(OCC(C)C)c2)ccc1N
Temperature: 80 °C

Procedure:
An iron apparatus equipped with horseshoe stirrer and heating and cooling means is charged with 293 g of o-nitro-isobutoxybenzene, 395 g of solvent naphtha and 220 g of zinc dust. The reaction mixture is heated with stirring to 80° C., and first 24 g of 50% strength sodium hydroxide solution and then 21 g of water are added with temporary cooling. To complete the reduction, stirring is continued at 80° C. with the addition of further zinc dust a little at a time (in total 53 g) until a spot test with the reaction solution shows a colorless runoff. By further addition of water the zinc oxide hydrate is then grained. The zinc oxide hydrate is then separated by filtration from the organic phase containing the 2,2'-diisobutoxyhydrazobenzene and as byproduct 1-isobutoxy-2-aminobenzene. After extraction of the byproduct with dilute hydrochloric acid the organic phase is added dropwise at 15°-20° C. to hydrochloric acid and stirring is continued at 25° C. until the rearrangement reaction has ended (test: hydrazo compound no longer detectable). The crude product is purified by filtration, dissolving in hot water and clarification of the solution with Carboraffin. Precipitation with concentrated hydrochloric acid gives 106 g of 3,3'-diisobutoxybenzidine dichlorohydrate having a diazotization value of 96%, melting point 270° C.
Reaction SMILES: [C:1]1([CH:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:14][CH:13]=2)[CH2:8][CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][NH:35][CH3:36])[CH3:31].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[CH2:30]([O:32][C:33](=[O:37])[CH2:34][N:35]([CH3:36])[CH2:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)=[CH:14][CH:13]=1)[CH3:31]
Reactant: FC(F)(F)c1cccc(Oc2ccc(OC(CCCl)c3ccccc3)cc2)c1
Reactant: CCOC(=O)CNC
Agent: Cl
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)CCC(Oc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1ccccc1
Temperature: 92.5 °C
Yield: 42.7 %

Procedure:
To a 125 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 486 mg (1.20 mmol) 3-phenyl-3-[4-(3-trifluoromethyl-phenoxy)-phenoxy]-1-chloropropane, 184 mg (1.20 mmol) sarcosine ethyl ester hydrochloride, 0.416 mL (2.40 mmol) diisopropylethylamine, and 6 mL dry N-methylpyrrolidinone. The reaction was heated at 90-95° C. for 60 h, cooled, and poured into water. After extracting with ethyl acetate, the organic layer was washed with water (3 times) and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methylene chloride/methanol as eluant to afford 250 mg (43%) of an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[N:17]1([C:22]2[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[N:18]1>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:28]([C:25]1[CH:24]=[CH:23][C:22]([N:17]2[CH:21]=[CH:20][CH:19]=[N:18]2)=[CH:27][CH:26]=1)(=[O:29])=[O:30])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccc(-n2cccn2)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-phenyl-methanone and 121 mg of 4-Pyrazol-1-yl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 6.47 (m, 1H), 7.25 (m, 2H), 7.30-7.35 (m, 3H), 7.41 (m, 1H), 7.49-7.55 (m, 3H), 7.67-7.72 (m, 3H), 7.75-7.78 (m, 2H), 9.62 (s, 1H). MS: m/z 438.9 (M++1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26](Cl)=[N:25][CH:24]=[CH:23][N:22]=1)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:20][C:21]1[C:26]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:25][CH:24]=[CH:23][N:22]=1)(=[O:18])=[O:19]
Reactant: OCc1cccnc1
Reactant: O=S(=O)(Nc1nccnc1Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1nccnc1OCc1cccnc1)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 28 using pyridine-3-methanol (0.09 g) and 2,3-dichloro-N-(3-chloro-2-pyrazinyl)benzenesulphonamide (0.1 g). Yield 0.042 g.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH:17]1([CH2:23][C:24](O)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:17]1([CH2:23][C:24]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(O)CC1CCCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 56 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-cyclohexylacetic acid (100 mg, 0.70 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-(cyclohexylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 56% yield (140 mg) as colorless oil.
Reaction SMILES: CC1C=CC(S(OCC2CC3C(C4C=CC=CC=4C)=CC=CC=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:33]([CH2:36][CH:37]1[CH2:41][C:40]2[C:42]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[CH3:52])=[CH:43][CH:44]=[CH:45][C:39]=2[O:38]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[CH3:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:42]1[C:40]2[CH2:41][CH:37]([CH2:36][NH2:33])[O:38][C:39]=2[CH:45]=[CH:44][CH:43]=1
Reactant: Cc1ccccc1-c1cccc2c1CC(CN=[N+]=[N-])O2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3C)O2)cc1
Agent: [N-]=[N+]=[N-]
Product: Cc1ccccc1-c1cccc2c1CC(CN)O2
Yield: 85 %

Procedure:
Treatment of (±)-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.31 g, 3.32 mmol) with sodium azide (0.863 g, 13.28 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-4-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.082 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.689 g (85%) of (±)-1-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 231-234° C.; Anal. calcd. for C16H17NOHCl.0.2H2O: C, 68.79; H, 6.64; N, 5.01. Found: C, 68.49; H, 6.50; N, 4.87.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([SH:8])[CH:7]=1.[Cl:11][C:12]([CH2:14]Cl)=[CH2:13]>CN(C)C=O>[Cl:9][C:5]1[C:6]([S:8][CH2:14][C:12]([Cl:11])=[CH2:13])=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: C=C(Cl)CCl
Reactant: Nc1cc(S)c(Cl)cc1F
Solvent: CN(C)C=O
Product: C=C(Cl)CSc1cc(N)c(F)cc1Cl
Yield: 83.2 %

Procedure:
A mixture of 5-amino-2-chloro-4-fluorothiophenol (8.89 g) and anhydride potassium carbonate (3.5 g) was dissolved in N,N-dimethylformamide (100 ml), and 2,3-dichloropropene (6.65 g) was added thereto. The resultant mixture was stirred at 20° to 40° C. for 4 hours. After completion of the reaction, the reaction mixture was extracted with ether,washed with water, dried and concentrated. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=7/1) to give 4-chloro-2-fluoro-5-(2-chloro-2-propenylthio)aniline (10.5 g; yield, 84%).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[F:25][C:26]([F:38])([F:37])[O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]([F:25])([F:37])[F:38])=[CH:33][CH:32]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) using 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester and 4-(trifluoromethoxy)phenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10](N(CC)CC)[CH3:11].CC(C)(O)C#C>ClCCl.C1(C)C=CC=CC=1.O.[Cu]I>[Br:9][C:5]1[CH:6]=[C:7]2[C:2](=[N:3][CH:4]=1)[NH:1][CH:11]=[CH:10]2
Reactant: Nc1ncc(Br)cc1I
Reactant: CCN(CC)CC
Agent: [Cu]I
Agent: C#CC(C)(C)O
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: Brc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.3 %

Procedure:
A suspension of 2-amino-5-bromo-3-iodopyridine (5.0 g, 16.7 mmol), bis-(triphenyl-phosphine)-palladium(II)-dichloride (43 mg, 0.061 mmol), copper(I)iodide (29.4 mg, 0.15 mmol) and triethylamine (2.21 g, 21.8 mmol) in dichloromethane (20 mL) was treated at 23 to 30° C. within 1 to 2 hours with a solution of 1,1-dimethyl-2-propyn-1-ol (1.85 g, 21.7 mmol) in dichloromethane (10 mL) and the resulting mixture was stirred at 25° C. for 4 hours. The mixture was diluted with dichloromethane (10 mL) and washed with water (2×25 mL). The organic phase was then treated with 1 M HCl (40 mL). The layers were separated and the organic layer was extracted with 1 M HCl (15 mL). The combined product containing aqueous layers were washed with dichloromethane (2×8 mL). The pH of the aqueous layer was adjusted to pH 7-9 by the drop wise addition of sodium hydroxide solution (28% in water). The resulting suspension was stirred at 20° C. over night and the crystals were then filtered off and washed with water (2×5 mL). The wet crystals were dissolved in N-methylpyrrolidone (50 mL) and treated within 2 hours at 60° C. and 50-100 mbar with an aqueous solution of lithium hydroxide (2.4 M, 32 mL). The resulting mixture was heated to 75° C. and stirred at this temperature and under reduced pressure (50-100 mbar) for 15-20 hours. Toluene (20 mL) and water (20 mL) were then added and the layers were separated. The aqueous layer was extracted with toluene (3×25 mL). The combined organic layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in N-methylpyrrolidone (50 mL) and treated at 60° C. with potassium tert.-butylate (3.52 g, 30.7 mmol). After stirring for 3 hours at 60° C., the mixture was cooled to ambient temperature and diluted with toluene (40 mL) and water (40 mL). The aqueous layer was separated and back extracted with toluene (3×50 mL). The combined toluene layers were washed with water (3×10 mL) and then concentrated to dryness. The residue was dissolved in a hot mixture of toluene and n-heptane (20 mL). The clear solution was cooled to −5° C. within 4 to 6 hours whereupon crystals precipitated. The suspension was stirred at −5° C. for 2-4 hours. The crystals were filtered off, washed with heptane and dried at 45° C./<30 mbars over night to afford 5-bromo-7-azaindole (2.05 g, 62% yield) as slightly yellow crystals with a purity of 99.6% (HPLC, area%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.S(Cl)([Cl:32])=O>ClCCl.CN(C)C=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]=[CH:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([Cl:32])=[O:24])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C=Cc2ccc(OCc3ccc4ccccc4n3)cc2)cc1

Procedure:
To 0.05 mol of 4-(4-(2-quinolinylmethyloxy)styryl) benzoic acid in dichloromethane solution (500 ml), chilled in an ice bath, is added thionyl chloride (0.06 mol) and a few drops of dimethylformamide. Upon completion of the reaction, the clear solution is evaporated to give 4-(4-(2-quinolinylmethyloxy)styryl)benzoyl choride.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:28]/[P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:4]=2[N:3]=1.[H][H]>C(Cl)Cl.CCO.[Pd]>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH2:27][CH2:28][P:29](=[O:36])([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOP(=O)(/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCOP(=O)(CCc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonate (3-1) (Example 10—Step 1) (1.0 equiv.) in DCM (0.05 M) and EtOH (0.08 M) was added 10% palladium on carbon (0.09 equiv.). A reaction vessel was charged with a hydrogen balloon and stirred at room temperature overnight. After the reaction was complete as monitored by LCMS, solvents were removed, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)ethylphosphonate (3-3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:16])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][Cl:21])=[C:8]([O:13][CH3:14])[CH:7]=1)[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)C(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)c1ccc(OCCCCl)c(OC)c1

Procedure:
A mixture of 1 mole of 4-hydroxy-3-methoxy-α-oxobenzeneacetic acid ethyl ester, 2 mole of 1-bromo-3-chloropropane and 3 mole of anhydrous potassium carbonate in 3 liters of acetone is heated at reflux for 20 hr. The mixture is cooled, filtered and the filtrate concentrated to give a solid residue. The solid is triturated with petroleum ether (30°-60° C.), collected by filtration and dried to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:11])[CH2:9]O)=[C:4]([F:12])[CH:3]=1.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:11])[CH2:9][N:17]2[C:13](=[O:23])[C:14]3[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:16]2=[O:18])=[C:4]([F:12])[CH:3]=1
Reactant: C[C@@H](CO)c1ccc(Br)cc1F
Reactant: O=C1NC(=O)c2ccccc21
Product: C[C@@H](CN1C(=O)c2ccccc2C1=O)c1ccc(Br)cc1F
Yield: 69 %

Procedure:
Following the procedure described for Example 633, (R)-2-(4-bromo-2-fluorophenyl)propan-1-ol (1.5 mg, 6.4 mmol) was reacted with phthalimide (1.0 mg, 7.008 mmol) to obtain the desired product (1.6 g, 69%) as a white solid: ESI MS m/z 363 [C17H13BrFNO2+H]+
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:9]=2[CH:10]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[S:31](=[O:33])(=[O:32])[CH2:30][CH2:29][C:28]([C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([CH2:43][N:44]([CH3:51])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[CH:39][CH:38]=3)=[O:35])=[CH:27][C:26]=2[CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:51][N:44]([CH2:43][C:40]1[CH:41]=[CH:42][C:37]([NH:36][C:34]([C:28]2[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[C:25]3[CH:24]=[CH:23][C:22]([C:6]4[O:7][C:8]5[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH3:18])=[CH:11][C:9]=5[CH:10]=4)=[CH:52][C:26]=3[CH:27]=2)=[O:35])=[CH:38][CH:39]=1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOc1ccc2oc(OB([O-])[O-])cc2c1
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: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc2oc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)cc2c1
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 5-propoxy-benzofuran-2-yl borate (165 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (750 ml) to give colorless crystals of N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-7-(5-propoxybenzofuran-2-yl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 139) (115 mg).