Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH2:4][N:5]([CH3:7])[CH3:6])[CH3:3].F[C:9](F)(F)C(O)=O.[CH3:15][N:16]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24](=[O:29])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2.CC1NC=CN=1.[OH-].[Na+]>>[CH3:15][N:16]1[C:28]2[CH2:27][CH2:26][CH:25]([CH2:7][N:5]3[CH:6]=[CH:3][N:2]=[C:4]3[CH3:9])[C:24](=[O:29])[C:23]=2[C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Reactant: CN(C)CN(C)C
Agent: Cc1ncc[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
At −10° C., 4 ml of N,N,N′,N′-tetramethyldiaminomethane was slowly added to 46 ml of trifluoroacetic acid, which was then stirred for 30 min. 2.0 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one and 8 g of 2-methyl imidazole was added to the reaction mixture, which was then stirred for about 8 hours at 120˜130° C. After completion of reaction, the reaction mixture was cooled at room temperature, and then 1N aq. sodium hydroxide was added thereto. The resulting solid was filtered and washed with water, and then dried. The resulting solid was suspended in 80 ml of methanol, and then 0.28 g of active carbon was added thereto, which was then stirred under reflux for 1 hour. The resulting mixture was filtered and washed with methanol, and then evaporated to give 2.2 g of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (yield 75%).
Reaction SMILES: [P:1]([O-:33])([O-:32])([O:3][C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:22][CH:21]=2)=[C:11](/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)\[CH2:12][CH3:13])=[CH:6][CH:5]=1)=[O:2].C(=O)([O-])O.[Na+:38]>>[P:1]([OH:33])([OH:32])([OH:3])=[O:2].[CH3:31][N:29]([CH3:30])[CH2:28][CH2:27][O:26][C:23]1[CH:22]=[CH:21][C:20](/[C:10](/[C:7]2[CH:6]=[CH:5][C:4]([Na:38])=[CH:9][CH:8]=2)=[C:11](\[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)/[CH2:12][CH3:13])=[CH:25][CH:24]=1
Reactant: [Na+]
Reactant: CC/C(=C(/c1ccc(OCCN(C)C)cc1)c1ccc(OP(=O)([O-])[O-])cc1)c1ccccc1
Agent: O=C([O-])O
Product: CC/C(=C(\c1ccc([Na])cc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Product: O=P(O)(O)O
Yield: 76.2 %

Procedure:
In a 2% aqueous solution of sodium hydrogen carbonate (20 ml) was dissolved Compound 1 (1.0 g) and the solution was applied to a column of MCI gel HP-20P (product of Mitsubishi Chemical Ind., Japan, high porous polymer). The column was washed with distilled water until the effluent became neutral and, then, elution was carried out with acetone-water (20:80). The eluate (500 ml) was concentrated to about 1/3 of its initial volume and lyophilized to give 0.8 g (yield 76.2%) of the title compound as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:26](Cl)=[O:27])[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2>>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1([C:26]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:27])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[O:19][C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: O=C(Cl)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: C1COCCN1
Product: O=C(N1CCOCC1)C1(CCCCBr)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from morpholine and 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid chloride.
Reaction SMILES: CO.O.[CH3:4][C:5]1([C:10]2[CH:11]=[C:12]([CH:16]3[N:21]4[CH:22]=[CH:23][N:24]=[C:20]4[NH:19][C:18]([CH3:25])=[C:17]3[C:26]([O:28][CH3:29])=[O:27])[CH:13]=[CH:14][CH:15]=2)OCC[O:6]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[C:5]([C:10]1[CH:11]=[C:12]([CH:16]2[N:21]3[CH:22]=[CH:23][N:24]=[C:20]3[NH:19][C:18]([CH3:25])=[C:17]2[C:26]([O:28][CH3:29])=[O:27])[CH:13]=[CH:14][CH:15]=1)(=[O:6])[CH3:4]
Reactant: COC(=O)C1=C(C)Nc2nccn2C1c1cccc(C2(C)OCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C1=C(C)Nc2nccn2C1c1cccc(C(C)=O)c1
Temperature: 60 °C
Yield: 69.8 %

Procedure:
In a mixture of 50 ml of acetone, 30 ml of methanol and 20 ml of water is dissolved 1.8 g of 5-[3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methoxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine. The mixture is adjusted to pH 1 with p-toluenesulfonic acid and then heated at 60° C. for 3 hours. The solvent is distilled off and the residue is neutralized with sodium bicarbonate solution. The resulting white precipitations are collected by filtration and recrystallized from a mixture of ethanol and acetone to give 1.1 g of 5-(3-acetylphenyl)-6-methoxycarbonyl-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine, melting at 227°-229° C.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12](=O)[CH3:13])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[N:17]=[C:18]([C:24]2S[CH:26]=[CH:27][CH:28]=2)S[C:20]=1[C:21](=O)[CH3:22].[NH3:29]>>[CH3:15][C@@H:16]1[CH2:20][CH2:21][CH2:22][N:17]1[CH2:18][CH2:24][C:28]1[CH:2]=[C:1]2[C:7](=[CH:26][CH:27]=1)[N:29]=[C:12]([C:10]1[O:9][N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:11]=1)[CH:13]=[CH:6]2
Reactant: CC(=O)c1cc(-c2ccccc2)no1
Reactant: N
Reactant: CC(=O)c1sc(-c2cccs2)nc1C
Product: C[C@@H]1CCCN1CCc1ccc2nc(-c3cc(-c4ccccc4)no3)ccc2c1

Procedure:
The title compound was prepared using the procedure described in Example 1G substituting 1-(3-phenyl-isoxazol-5-yl)-ethanone (Ohsawa, A. et. al. Heterocycles 1978, 9, pages 1367–1373) for 1-(4-methyl-2-thiophen-2-yl-thiazol-5-yl)-ethanone. 1H NMR (300 MHz, CD3OD) δ 1.18 (d, J=6 Hz, 3H), 1.50 (m, 1H), 1.82 (m, 2H), 2.04 (m, 1H), 2.39 (q, J=6 Hz, 1H), 2.52 (m, 2H), 3.08 (m, 2H), 3.22 (m, 2H), 7.53 (m, 3H), 7.64 (s, 1H), 7.78 (dd, J=9 Hz, J=3 Hz, 1H), 7.85 (s, 1H), 7.99 (m, 2H), 8.10 (dd, J=9 Hz, J=3 Hz, 2H), 8.45 (d, J=9 Hz, 1H); MS (DCI/NH3) m/z 384 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Cr](O)(O)(=O)=O.C(N(CC)CC)C.[OH2:25].[O:26]1[CH2:30]CCC1>S(=O)(=O)(O)O.CO>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([Cl:1])[N:3]=[C:4]([C:12]([O:26][CH3:30])=[O:25])[CH:5]=1
Reactant: C1CCOC1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: O
Agent: O=[Cr](=O)(O)O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Yield: 69 %

Procedure:
2,4-Dichloro-6-methyl-3-nitropyridine (15.0 g, 72.5 mmol) was dissolved in concentrated sulfuric acid (73 mL) under ice-cold conditions and added with chromic acid (21.7 g, 217 mmol). The resultant mixture was stirred overnight by gradually warming to room temperature. After completion of the reaction, ice water was added under ice-cold conditions and the resultant mixture was filtered. Tetrahydran was added thereto, and the resultant mixture was concentrated in vacuo to obtain a crude product (15.7 g). The obtained crude product (15.7 g) was dissolved in tetrahydrofuran (180 mL) and methanol (180 mL). The reaction solution was added with triethylamine (90 mL, 652 mmol) and methyl ester chloroformate (34 mL, 435 mmol) under ice-cold conditions, and the resultant mixture was stirred for 10 minutes. After completion of the reaction, water was added, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (chloroform/methanol), and methyl 4,6-dichloro-5-nitropicolinate (12.6 g, yield 69%) was obtained as a yellow crystal.
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:17]=3)=[CH:14][N:15]=[C:9]2[CH:8]=1)=O.O.[NH2:33]N>C(O)(=O)C>[N:2]1[N:33]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:19]=[CH:20][CH:21]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)[NH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4nnc[nH]4)ccn23)c1
Temperature: 90 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 3-{3-[3-(2,2,2-Trifluoro-ethyl)-ureido]-phenyl}-imidazo[1,2-a]pyridine-7-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamide (17 mg, 0.04 mmol) in acetic acid (0.5 ml) was added hydrazine hydrate (5 μl, 0.1 mmol). The reaction mixture was heated at 90° C. for 30 min before being cooled to room temperature. The volatiles were removed in vacuo and the residue azeotroped with toluene. Trituration of the residue with Et2O afforded a pink solid (12 mg). MS: [M+H]+ 402.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[N+:18]([O-])([OH:20])=[O:19]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([OH:17])=[C:6]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(-c2cc(Cl)ccc2O)n1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-c2cc(Cl)cc([N+](=O)[O-])c2O)n1

Procedure:
To the solution of 6-(5-chloro-2-hydroxyphenyl)-pyridine-2-carboxylic acid; (2.3 g, 10.1 mmol) in 100 ml acetic acid; was added 1 ml fuming nitric acid; and stirred at 35° C. to 40° C. for half an hour. The reaction mixture was diluted with water and adjusted pH to 2.5. The resulting precipitation was collected, washed and dried to give solid (2.74 g; 78%, three steps). MS (ES) m/z 295 [M+H].
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]([CH2:26]Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:26][CH:20]1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 67.1 %

Procedure:
To a solution of N1,N2-dibenzylethane-1,2-diamine (24 g, 100 mmol) in toluene (100 mL) was added TEA (24.2 g, 240 mmol). The mixture was heated to 80° C., and a solution of ethyl 2,3-dibromopropanoate (27.3 g, 105 mmol) in toluene (100 mL) was added dropwise over a period of 0.5 hour at 80° C. Then the mixture was stirred at the temperature for 12 hours and cooled to 25° C. The reaction mixture was washed with saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=5/1) to give the title compound as yellow oil (22.7 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13]Cl.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[O:18]1[CH2:19][CH2:20][N:15]([CH2:11][CH2:12][CH2:13][O:9][C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCCCN2CCOCC2)cc1

Procedure:
According to a similar manner as that in Reference Example 78 except that 4-cyanophenol, 1-bromo-3-chloropropane, and morpholine were used, 4-(3-morpholinopropoxy)benzonitrile (quantitative) was obtained as a crude product.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.Cl[CH2:21][C:22]1[N:26]=[C:25]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=2)[O:24][N:23]=1>>[F:33][C:31]1[CH:32]=[C:27]([C:25]2[O:24][N:23]=[C:22]([CH2:21][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:3][CH:2]([CH3:19])[CH3:1])[N:26]=2)[CH:28]=[C:29]([F:34])[CH:30]=1
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.3 Hz, 1H), 7.56 (m, 3H), 7.05 (t, J=8.5 Hz, 1H), 6.63 (s, 1H), 5.46 (s, 2H), 2.83 (d, J=7.1 Hz, 2H), 2.13 (m, 1H), 1.07 (d, J=6.6 Hz, 6H); MS (ES) m/z 461 (M+1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH:25][CH3:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6].[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([OH:13])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH:22]=[CH:23][CH:24]=[CH:25][CH3:26])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH:2]=[CH:3][CH:4]=[CH:5][CH3:6]
Reactant: Br[Mg]c1ccccc1
Reactant: CC=CC=CCOc1ccc(C(=O)c2ccc(OCC=CC=CC)cc2)cc1
Solvent: C1CCOC1
Product: CC=CC=CCOc1ccc(C(O)(c2ccccc2)c2ccc(OCC=CC=CC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
Compound 35 (2.0 grams) was dissolved in THF (45 mL) and phenylmagnesium bromide (1.0M solution in THF; 10.6 mL, 10.6 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 3 hours, and evaporated to dryness under vacuum. The residue was redissolved in dichloromethane and washed with a saturated solution of ammonium chloride, followed by water. The organic phase was dried (MgSO4), concentrated in vacuo and purified column chromatography (silica gel; hexane/CH2Cl2, 1/9) to afford 1.84 grams (77%) of compound 36 as a pale yellow solid. 1H NMR (300 MHz, DMSO-d6) δ1.73 (d, J=6.9 Hz, 6H), 4.54 (d, J=6.0 Hz, 4H), 5.68-5.80 (m, 4H), 6.02, 6.11 (m, 2H), 6.20-6.37 (m, 2H), 6.85 (d, J=6.9 Hz, 4H), 7.05 (d, J=7.0 Hz, 4H), 7.14-7.32 (m, 5H); Anal. Calcd for C31H32O3 (452.5920): C, 82.27; H, 7.13; Found: C, 82.30; H, 7.11.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:54]1[CH:59]=[C:58](B(O)O)[CH:57]=[N:56][CH:55]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=4)=[C:15]([C:58]4[CH:59]=[N:54][CH:55]=[N:56][CH:57]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C1C(Br)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Reactant: OB(O)c1cncnc1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cncnc2)=C(c2ccc(Cl)cc2)c2ccc(OCCN3CCOCC3)cc21
Yield: 71 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(4-chlorophenyl)-1H-inden-1-one obtained in Step 6 of Example 28 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (acetone/hexanes=2:3) to obtain the title compound (71%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]([F:32])([F:31])[F:30])[CH2:25][CH2:24]3)=[CH:19][CH:18]=2)[N:5]=[C:4]([N:33]2[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]([O:44]CC)=[O:43])[CH:35]=[N:34]2)[CH:3]=1.[C:47]([O-:50])([O-])=[O:48].[K+].[K+].[CH3:53]B1OB(C)OB(C)O1>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.O1CCOCC1>[C:47]([OH:50])([C:29]([F:32])([F:31])[F:30])=[O:48].[CH3:53][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C@H:23]3[CH2:24][CH2:25][C@H:26]([C:29]([F:30])([F:31])[F:32])[CH2:27][CH2:28]3)=[CH:19][CH:18]=2)[N:5]=[C:4]([N:33]2[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]([OH:44])=[O:43])[CH:35]=[N:34]2)[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)c1cnn(-c2cc(I)cc(-c3cc(C)ccc3OCc3ccc([C@H]4CC[C@H](C(F)(F)F)CC4)cc3)n2)c1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(-c2cc(C)ccc2OCc2ccc([C@H]3CC[C@H](C(F)(F)F)CC3)cc2)nc(-n2ncc(C(=O)O)c2C(F)(F)F)c1
Product: O=C(O)C(F)(F)F
Temperature: 140 °C

Procedure:
A mixture of the title compound from Example 19 Step I (20 mg, 0.026 mmol) Pd(PPh3)4 (10.7 mg, 0.009 mmol), K2CO3 (11 mg, 0.08 mmol), trimethyl boroxine (11.6 mg, 0.09 mmol), and dioxane (0.5 mL) was heated in a microwave reactor at 140° C. for 1 h, cooled, diluted with hexanes and passed through a pad of silica gel eluted by dichloromethane. The solvent was removed in vacuo. Treatment with a mixture of 1,4-dioxane (0.1 mL), MeOH (0.1 mL) and 3 N NaOH (0.1 mL) at 50° C. for 15 min, followed by reverse phase HPLC using a YMC C-18 column (45 to 95% acetonitrile in water, each with 0.1% v/v TFA) provided the title compound: LCMS m/z 618.8 [M+H]+; 1H NMR (400 MHz, acetone-d6), δ 8.17 (s, 1H), 8.08 (s, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.48 (s, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.20 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 2.43 (s, 3H), 2.29 (s, 3H), 2.59 (m, 1H), 1.96 (m, 2H), 1.67-1.39 (m, 4H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=4)=[CH:17][C:12]=3[CH:11]=[C:10]([C:31]([O:33]C)=[O:32])[CH2:9][CH2:8]2)=[CH:2]1.[OH-].[Na+].O.Cl>O1CCCC1.CO>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=4)=[CH:17][C:12]=3[CH:11]=[C:10]([C:31]([OH:33])=[O:32])[CH2:9][CH2:8]2)=[CH:2]1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 87.5 %

Procedure:
To a solution of methyl 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (362 mg) in a mixture of tetrahydrofuran (24 ml) and methanol (24 ml) was added 1N sodium hydroxide solution (8 ml), and the mixture was stirred at room temperature for 5 days. Then, to the mixture was added water at −0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was washed with hexane to give 1-(3-furylmethyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (307 mg) as yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([NH:15][C@H:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:17][CH3:18])=[O:14])=[CH:10][CH:9]=[CH:8][CH:7]=2.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:19]1([C@@H:16]([NH:15][C:13]([C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:3]=2[CH2:2][NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[O:14])[CH2:17][CH3:18])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC[C@H](NC(=O)c1c(CN)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1c(CNS(C)(=O)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of 3-(aminomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (2e) (197 mg, 0.5 mmol) in DCM (30 ml) was added triethylamine (140 μL, 1.0 mmol) under N2. Upon cooling with ice-water bath, methanesulfonyl chloride (39 μL, 0.51 mmol) was added dropwise and the reaction mixture stirred at RT for additional 2 h. Washed the mixture with brine (10 mL) and the organic phase was separated and dried over sodium sulfate and then concentrated in vacuo. The residue was purified by chromatography eluting with 15-25% ethyl acetate/hexane to give the title compound (79 mg, 42%) as a solid. 1H NMR (300 MHz, CDCl3) δ 0.94 (t, 3H), 1.95 (m, 2H), 2.99 (s, 3H), 4.88 (s, 2H), 5.25 (q, 1H), 6.66 (b, 2H), 7.30 (d, 2H), 7.34 (d, 2H), 7.39 (m, 1H), 7.78 (m, 2H), 7.84 (m, 2H), 8.08 (m, 1H), 8.30 (m, 2H), 8.20 (m, 2H). MS APCI, m/z=474 (M+1). LCMS: 2.16 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:53])([CH3:52])[CH2:9]/[CH:10]=[CH:11]/[C:12](=[O:51])[N:13]([CH3:50])[C@@H:14]([C:26](=[O:49])[N:27]([CH3:48])[C@@H:28]([C:36](=[O:47])[N:37]([CH3:46])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].O>ClCCl>[CH3:50][N:13]([C@@H:14]([C:26](=[O:49])[N:27]([CH3:48])[C@@H:28]([C:36](=[O:47])[N:37]([CH3:46])[CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[C:12](=[O:51])/[CH:11]=[CH:10]/[CH2:9][C:8]([NH2:7])([CH3:52])[CH3:53]
Reactant: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N
Temperature: -10 °C
Reaction time: 0.75 h
Yield: 70.1 %

Procedure:
((3E)-1,1-Dimethyl-4-{N-methyl-N-[(1R)1-(N-methyl-N-{(1R)-1-[N-methyl-N-(2-(pyridin-2-yl)ethyl)carbamoyl]-2-phenylethyl}carbamoyl)-2-(2-naphthyl)ethyl]carbamoyl}but-3-enyl)carbamic acid tert-butyl ester (5.28 g, 7.2 mmol) was dissolved in dichloromethane (50 mL). The solution was cooled to −10° C. Trifluoroacetic acid (50 mL) was added to the stirred solution. The reaction mixture was stirred for 45 min at −10° C. The reaction mixture was added to a solution of ice, sodium hydrogen carbonate and water. The reaction mixture was neutralised with sodium hydrogen carbonate. Dichloromethane (400 mL) was added. The aqueous phase was extracted with dichloromethane (300 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using 15% of a solution, 7% ammonium in ethanole, in dichloromethane as eluent, to give 3.2 g of the title compound.