Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:16]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>>[O-:36][N+:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:6]2[N:5]([CH2:17][CH2:18][CH2:19][C:20](=[O:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]([CH2:1][CH2:2][CH3:3])=[N:16][C:7]=2[CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCC(=O)CCCn1c(CCC)nc2cnc3ccccc3c21
Product: CCCCCCC(=O)CCCn1c(CCC)nc2c[n+]([O-])c3ccccc3c21

Procedure:
The general method described in Parts I and J of Example 28 was used to aminate 1-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one (6.10 g, 17.2 mmol) by reaction with m-CPBA (8.50 g) to provide 1-(5-oxido-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one followed by reaction with p-toluenesulfonyl chloride (4.90 g, 25.8 mmol) and ammonium hydroxide solution (100 mL) to provide 1-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)decan-4-one) as a white solid after recrystallization from aqueous methanol, mp 111-113° C.
Reaction SMILES: C1COCC1.[F:6][C:7]1[CH:8]=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([O:15][CH3:16])=[C:11]([CH2:13]O)[CH:12]=1.S(Cl)([Cl:27])=O.CN(C=O)C>C(OCC)(=O)C>[Cl:27][CH2:13][C:11]1[CH:12]=[C:7]([F:6])[CH:8]=[C:9]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]=1[O:15][CH3:16]
Reactant: O=S(Cl)Cl
Reactant: COc1c(CO)cc(F)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(CCl)cc(F)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
A THF (25 mL) solution of {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}methanol (6.94 g, 26 mmol) was cooled to 0° C. and was then treated with thionyl chloride (2.5 mL, 34 mmol) and DMF (5.0 mL, 65 mmol) for 30 min. Ethyl acetate and ice water were then added. The layers were partitioned, and the aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product, 1-(chloromethyl)-5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene, was obtained as an orange oil (6.82 g, 24.3 mmol, 93% yield), which solidified upon storage in the freezer. 1H NMR (400 MHz, CDCl3): δ 7.45-7.26 (m, 5H), 6.72-6.66 (m, 2H), 5.09 (s, 2H), 4.61 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH2:25].C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:25]([CH2:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[O:15][CH3:14])[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(Br)ccc3C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
To a solution of methyl 4-bromo-2-(bromomethyl)benzoate (1.0 g, 3.25 mmol) and (2,4-dimethoxyphenyl)methanamine (0.65 g, 3.90 mmol) in THF (16 mL) was added triethylamine (0.91 mL, 6.5 mmol), and the resulting mixture was stirred at room temperature for 16 h. The resulting solid was filtered off, and the filtrate was concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 1:4 EtOAc:hexanes as the eluent to give the title compound as a colorless solid (0.52 g, 44%).
Reaction SMILES: [CH:1]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>CN1CCCC1=O.C(OCC)(=O)C>[O:33]=[C:24]1[C:25]2[C:26](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:28])[N:23]1[CH2:22][CH2:21][CH2:20][N:4]([CH:1]([CH3:3])[CH3:2])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6]
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)N(CCCN1C(=O)c2ccccc2C1=O)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 73 %

Procedure:
The compound (6.29 g, 25.75 mmol) obtained in step A was dissolved in N-methylpyrrolidone (100 ml), and the mixture was stirred under ice-cooling. Thereto was added 60% sodium hydride (1.21 g, 30 mmol) and the mixture was stirred at room temperature for 20 min. After stirring, N-(3-bromopropyl)phthalimide (8.31 g, 31.0 mmol) was added and the mixture was stirred at 70° C. for 90 min. The reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained solid was washed with diethyl ether-hexane mixed solvent, and dried under reduced pressure to give the title compound (8.11 g, yield 73%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:8][S:9]([O:1][CH2:2][C:3]1([C:6]#[N:7])[CH2:5][CH2:4]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC1(CO)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(C#N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At r.t. to a solution of 1-(hydroxymethyl)cyclopropanecarbonitrile (0.41 g, 4.2 mmol) in methylene chloride (10 mL) was added methanesulfonyl chloride (490 uL, 6.3 mmol), followed by triethylamine (1.5 mL, 10.0 mmol) and 4-dimethylaminopyridine (18 mg, 0.15 mmol). The mixture was stirred at r.t. for 3 h. It was diluted with methylene chloride, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield the crude product which was used in the next step reaction without further purification.
Reaction SMILES: Br[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:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol (Enantiomer B) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]\[C:11]([O:13]CC)=O)=[CH:4][C:3]=1[O:22][CH3:23]>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:22][CH3:23])[NH:8][C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:10][C:11]2=[O:13]
Reactant: CCOC(=O)/C=C(\Nc1ccc(Br)c(OC)c1)c1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2[nH]c(-c3ccccc3)cc(=O)c2cc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 82.8 %

Procedure:
To refluxing (˜300° C.) dowtherm A (100 ml) (mixture of biphenyl and diphenyl ether) was added ethyl (2Z)-3-[(4-bromo-3-methoxyphenyl)amino]-3-phenylacrylate (6.5 g, 17.27 mmol) in DOWTHERM A (5 mL, washed with 1 mL). Almost immediately, white solid begins to precipitate out of solution. Refluxing was continued for 40 min, and the reaction was cooled to RT and let stand for 1 h. The white solid was then filtered off, and the washed extensively with hexanes to give 6-bromo-7-methoxy-2-phenylquinolin-4(1H)-one as white crystals (4.72 g, 83%). 1H NMR (400 MHz, DMSO-d6): 11.69 (s, 1H), 8.19 (s, 1H), 7.82 (m, 2H), 7.59 (m, 3H), 7.35 (s, 1H), 6.33 (s, 1H), 3.96 (s, 3H). LRMS (CI, [M+H]) Calc'd=330.0. found=330.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:42][CH:43]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:47]([CH2:59][NH2:60])[CH:46]=1)[OH:44])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:16][CH:17]([OH:34])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([CH2:32][NH2:33])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:61][S:62](Cl)(=[O:64])=[O:63].Cl>N1C=CC=CC=1>[CH2:35]([N:15]([CH2:16][CH:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([CH2:32][NH:33][S:62]([CH3:61])(=[O:64])=[O:63])[CH:19]=1)[OH:34])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:42][CH:43]([OH:44])[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)=[C:47]([CH2:59][NH:60][S:62]([CH3:61])(=[O:64])=[O:63])[CH:46]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cc(C(O)CN(CCCCCCN(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(CN)c2)Cc2ccccc2)ccc1OCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NCc1cc(C(O)CN(CCCCCCN(Cc2ccccc2)CC(O)c2ccc(OCc3ccccc3)c(CNS(C)(=O)=O)c2)Cc2ccccc2)ccc1OCc1ccccc1

Procedure:
To a solution of 9.35 g. of N,N'-dibenzyl-N,N'-bis[2-(3-aminomethyl-4-benzyloxyphenyl)-2-hydroxyethyl]-hexamethylenediamine in 50 ml. of pyridine is added 2.5 ml. of methanesulfonyl chloride at room temperature. After 18 hours the reaction mixture is added to an excess of 2N hydrochloric acid and extracted with chloroform. The extract is neutralized with sodium bicarbonate, washed, dried and evaporated to give N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methanesulfonamidomethylphenyl)-2-hydroxyethyl]-hexamethylenediamine. The latter, as the dihydrochloride, is hydrogenated with palladium-on-carbon to yield N,N'-bis[2-(4-hydroxy-3-methanesulfonamidomethylphenyl)-2-hydroxyethyl]-hexamethylenediamine dihydrochloride.
Reaction SMILES: [CH3:1][C:2](=[CH2:35])[CH2:3][C@:4]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:10][CH2:9][CH2:8][N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[C:6](=[O:28])[NH:5]1.I[C:37]1[CH:42]=[CH:41][N:40]([CH3:43])[C:39](=[O:44])[CH:38]=1>>[CH3:43][N:40]1[CH:41]=[CH:42][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:8][CH2:9][CH2:10][C@:4]([CH2:3][C:2]([CH3:1])=[CH2:35])([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:5][C:6]3=[O:28])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][C:39]1=[O:44]
Reactant: Cn1ccc(I)cc1=O
Reactant: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C(=O)N1
Product: C=C(C)C[C@]1(c2ccccc2)CCCN([C@@H](C)c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)N1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 10 Step 3 using (S)-4-(2-methylallyl)-4-phenyl-1-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-diazepan-2-one and 4-iodo-1-methylpyridin-2(1H)-one.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1>>[BrH:8].[CH3:1][C@H:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7]1
Reactant: C[C@@H]1CNCCN1
Reactant: Brc1ccccn1
Product: Br
Product: C[C@@H]1CN(c2ccccn2)CCN1
Temperature: 23 °C
Yield: 99.9 %

Procedure:
A solution of (R)-(−)-2-methylpiperazine (0.50 g, 0.005 mol, CAS 75336-86-6, Aldrich 39,716-4, 99%) and 2-bromopyridine (5 mL, 0.05 mol) was heated to 120° C. for 14 hours. The reaction mixture was cooled to 23° C. and partitioned between a large volume of ethyl acetate and water. The layers were separated, and then additional water was added to the ethyl acetate solution. Drops of 1N Hydrochloric acid solution were added to the water/ethyl acetate mixture with vigorous mixing until all of the product was transferred to the aqueous phase. The layers were separated, and the combined aqueous phases concentrated under reduced pressure, and azeotroped with toluene/methanol (5×) to afford 1.29 g (>99% yield) of 3-(R)-methyl-1-pyridin-2-yl-piperazine hydrobromide. 1H NMR (300 MHz, DMSO-d6) δ 1.27 (d, J=6.6 Hz, 3H), 2.90 (dd, J=10.5, 14.1 Hz, 1H), 3.10 (m, 2H), 3.40 (m, 2H), 4.32 (m, 2H), 6.77 (dd, J=4.8, 6.9 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 7.64 (m, 1H), 8.15 (m, 1H), 8.63 (br s, 1H), 8.92 (br s, 1H); MS (ESI) m/e 178 (M+H)+.
Reaction SMILES: C([NH:9][C:10](=[S:35])[NH:11][CH2:12][C:13]1[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)=[N:15][C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:17][C:18]=1[CH3:19])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O>[CH3:19][C:18]1[N:17]=[C:16]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:15]=[C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)[C:13]=1[CH2:12][NH:11][C:10]([NH2:9])=[S:35]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CNC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CNC(N)=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A mixture of 5-(3-benzoylthioureidomethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.0 g) and sodium hydroxide (0.089 g) in methanol (20 ml) and water (10 ml) was stirred for 1 hour at a room temperature. After evaporating the solvent, water (20 ml) was added thereto and stirred for 30 minutes. The resulting precipitates were collected by filtration, washed with water and dried over phosphorous pentoxide to give 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-thioureidomethylpyrimidine (0.75 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:25]=[C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=1)[CH3:27]>CN(C=O)C.[Cu]I>[F:36][C:30]1[CH:29]=[C:28](/[C:26](/[CH3:27])=[CH:25]/[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:33]=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: COc1ccc(C(C)=CBr)cc1F
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(/C(C)=C/n2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (68 mg, 0.34 mmol) was dissolved in DMF (3 mL). Copper (I) iodide (6.5 mg, 0.034 mmol) L-proline (7.8 mg, 0.068 mmol) and potassium phosphate (144 mg, 0.68 mmol) were added and the reaction mixture was stirred for min. at RT. 4-(1-Bromoprop-1-en-2-yl)-2-fluoro-1-methoxybenzene (100 mg, 0.408 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. (prolonged heating in some cases was required). DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). 1H NMR (CD3OD, HCl salt) δ (ppm): 7.42 (m, 2H), 7.30 (s, 1H), 7.18 (d, 1H), 7.10 (m, 2H), 7.0 (s, 1H), 4.75 (m, 1H), 4.40 (m, 1H), 3.95 (s, 3H), 3.85 (m, 1H), 3.60 (m, 1H), 3.20 (m, 2H), 3.10 (s, 3H), 2.42 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]4CCCC(C=O)[C:13]4([CH3:23])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:24]1[C:37]2[C:28](=[CH:29][C:30]3[C:35]([C:36]=2[CH:38]=O)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:27]=[CH:26][CH:25]=1.[CH2:40]1[CH2:44][O:43][CH2:42][CH2:41]1>>[CH:34]1[C:35]2[C:30](=[CH:29][C:28]3[C:37]([C:36]=2[CH:38]=[C:40]2[C:44](=[O:43])[C:13]4([CH3:12])[CH2:23][C:11]5[CH:10]=[N:9][N:8]([C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)[C:16]=5[CH:15]=[C:14]4[CH2:42][CH2:41]2)=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:31]=[CH:32][CH:33]=1
Reactant: C1CCOC1
Reactant: CC12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCCC2C=O
Reactant: O=Cc1c2ccccc2cc2ccccc12
Product: CC12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCC(=Cc1c3ccccc3cc3ccccc13)C2=O
Temperature: 0 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
In a 100 mL round bottom flask, aldehyde (207) (100 mg, 0.337 mmol) and anthracene-9-carboxaldehyde (349 mg, 1.69 mmol) were dissolved in 10 mL THF and cooled to 0° C. Lithium hexamethyldisilylamide (LHMDS) (370 μL, 0.370 mmol) was added dropwise, and the solution was stirred at room temperature for 16 hours. The reaction was quenched with 5 mL of saturated aqueous ammonium chloride. The aqueous layer was extracted with ether (3×10 mL), and the pooled organic extracts were washed with brine (10 mL), dried (MgSO4) and then concentrated. Flash chromatography of the residue (0-25% EtOAc/hexanes) gave (269) (127.9 mg, 78%). 1H NMR (CDCl3) δ 1.45 (s, 3 H) 2.19 (m, 1 H) 2.35 (m, 2 H) 2.47 (m, 1 H) 3.04 (d, J=16.11 Hz, 1 H) 3.15 (d, J=16.11 Hz, 1 H) 6.25 (s, 1 H) 7.13 (t, J=8.55 Hz, 2 H) 7.47 (m, 6 H) 7.55 (s, 1 H) 7.87 (m, 1 H) 8.00 (m, 3 H) 8.39 (s, 1 H) 8.43 (s, 1 H); 13C NMR (CDCl3) 23.5, 27.2, 29.7, 30.2, 49.4, 110.4, 114.0, 115.9, 116.1, 125.0, 125.1, 125.2, 125.3, 125.5, 126.1, 127.5, 128.8, 128.9, 128.9, 129.0, 129.7, 131.1, 131.1, 135.5, 135.7, 135.7, 136.4, 138.5, 139.1, 145.2, 160.2, 162.6, 202.8.
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.O.NN.C([OH:26])C.[OH-].[Na+]>O.C(O)COCCO>[N:12]1[C:6]2[O:5][C:4]3[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:26])=[CH:16][C:3]=3[CH2:2][CH2:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Reactant: CCO
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 18 %

Procedure:
A mixture of 20 mg of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetamide, 0.5 ml of hydrazine hydrate and 1.5 ml of ethanol was refluxed for 1 hour. The solvent and excess hydrazine hydrate were removed by distillation to obtain a residue, to which was added ethanol. Thereafter, the solvent was distilled off to obtain a yellow oil, to which were added 0.1 g of sodium hydroxide and 3 ml of dry diethylene glycol. The mixture was stirred at 100° C. for 20 minutes and then at 120° C. for 2.5 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was chromatographed over 1 g of silica gel and eluted with chloroform, thereby yielding 3.5 mg (yield: 18%) of (5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 203°-204° C.
Reaction SMILES: [F:1][C:2]([F:28])([O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=1)[C@H:3](OS(C(F)(F)F)(=O)=O)[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH2:34][S:35][C:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]([OH:33])=[O:32]>C(Cl)Cl>[F:28][C:2]([F:1])([O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26][CH3:27])=[CH:24][CH:25]=1)[C@@H:3]([NH:29][C@@H:30]([CH2:34][S:35][C:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:31]([OH:33])=[O:32])[C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CSc1ccc(OC(F)(F)[C@H](OS(=O)(=O)C(F)(F)F)c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: CSc1ccc(OC(F)(F)[C@@H](N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 27.6 %

Procedure:
A mixture of trifluoromethanesulfonic acid 2,2-difluoro-1(R)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethyl ester (1.70 g, 3.8 mmol), 2(R)-amino-3-tritylsulfanylpropionic acid (1.38 g, 38 mmol) and diisiopropylethylamine (2.65 ml, 15.2 mol) in DCM (35 ml) was stirred for 19 h at room temperature. The solvent was evaporated under vacuum and the residue dissolved in ethyl ether (20 ml). The solution was washed with 1N HCl solution and brine. After drying over sodium sulfate, the solvent was evaporated and the crude was purified by flash chromatography, using a mixture of EA/H (1/3) as eluent to give 2(R)-[2,2-difluoro-1(S)-(4-fluorophenyl)-2-(4-methylsulfanylphenoxy)ethylamino]-3-tritylsulfanylpropionic acid (0.693 g, 27%) as a foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([NH2:17])[C@H:13]([O:18][CH3:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([N:25]2[CH2:31][C:30]([F:33])([F:32])[C:29](=[O:34])[N:28]([CH3:35])[C:27]3[CH:36]=[N:37][C:38]([NH:40][C:41]4[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][C:42]=4[O:50][CH3:51])=[N:39][C:26]2=3)[CH2:24][CH2:23][CH2:22][CH2:21]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:45](=[O:46])[C:44]2[CH:48]=[CH:49][C:41]([NH:40][C:38]3[N:37]=[CH:36][C:27]4[N:28]([CH3:35])[C:29](=[O:34])[C:30]([F:32])([F:33])[CH2:31][N:25]([CH:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)[C:26]=4[N:39]=3)=[C:42]([O:50][CH3:51])[CH:43]=2)[CH:13]([O:18][CH3:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1N
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C(=O)OCc3ccccc3)CC2OC)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
A mixture of 0.058 g (0.22 mmole) of (rac)-(3R,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid benzyl ester, 0.089 g (0.20 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.083 g (0.22 mmole) 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate, 0.057 g (0.44 mmole) of diisopropylethylamine and 2 mL of dimethylformamide was stirred at room temperature for 1 hour. The mixture was poured into 50 mL of water and extracted three times with 25 mL of ethyl acetate. The combined organic extracts were washed three times with 25 mL of water, once with 25 mL of saturated aqueous ammonium chloride solution, once with 25 mL of saturated aqueous sodium bicarbonate solution, once with 25 mL of brine and dried over anhydrous magnesium sulfate. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2) to give 0.081 g of rac-(3R,4R)-4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-3-methoxy-piperidine-1-carboxylic acid benzyl ester (I-55) as a foam. Tritruration of the foam with diethyl ether gave a white solid.