Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1.[H-].[Na+].[Cl-].[CH2:30]([NH2:33])[C:31]#[CH:32]>CN(C)C=O.O>[CH2:30]([NH:33][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1)[C:31]#[CH:32]
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Reactant: C#CCN
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.2 %

Procedure:
To a solution of 0.71 g of 4-hydroxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 5 ml of dimethylformamide was added 0.090 g of sodium hydride (60% oily), and this was stirred at room temperature for 1 hour. 0.46 g of paratoluenesulfonyl chloride was added thereto, this was stirred at room temperature for 4 hours, then, 0.60 g of propargylamine was added, and this was stirred at room temperature overnight. To the reaction solution was added water, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 0.080 g of 4-propargylamino-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (13b)] as a yellow crystal.
Reaction SMILES: [CH3:1][N:2]([CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([O:69]C(C)(C)C)=[O:68])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1)=[O:4].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]([CH2:56][CH2:57][O:58][CH2:59][CH2:60][O:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][C:67]([OH:69])=[O:68])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][CH2:11][N:12]([CH3:55])[C:13](=[O:54])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[O:53])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:24][C:23]=2[C:34]2[CH:39]=[C:38]([C:40](=[O:52])[NH:41][C@@H:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH2:45][CH2:44][CH2:43]3)[CH:37]=[CH:36][N:35]=2)[CH:15]=1)=[O:4]
Reactant: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.5 %

Procedure:
To tert-Butyl 2-methyl-1-((S)-1-(2-(N-methyl-3-((4-(piperidin-1-yl)-2-(4-(((S)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzamido) ethyl) pyrrolidin-2-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate (16 mg) was added TFA (2 mL). The mixture was stirred at rt for 30 minutes, concentrated and purified by prep. HPLC to give a yellow solid (17.6 mg, 86%). MS (ES, m/z): 946.34 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH:30]=[CH2:31]>O>[CH2:31]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:2][CH2:3]1)[CH:30]=[CH2:29]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCN(c2ccc3c(c2)CCC(=O)N3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a mixture of 1 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 15 ml of DMF and 1.82 g of potassium carbonate was added 500 mg of allyl bromide and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Then, chloroform was distilled off and the residue was purified through silica gel column chromatography and recrystallized from chloroform-ether to give 0.43 g of 6-(4-allyl-1-piperazinyl)-3,4-dihydrocarbostyril, m.p. 175°-176° C., colorless scales.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]([O:12][CH:13]1[CH2:17][CH:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][CH:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[CH:24]1)(=[O:11])[CH3:10]>CN(C)C=O>[C:9]([O:12][CH:13]1[CH2:17][CH:16]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:15][CH:14]1[N:23]1[C:27]2[CH:28]=[C:29]([Cl:33])[C:30]([Cl:32])=[CH:31][C:26]=2[N:25]=[C:24]1[Br:1])(=[O:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)OCC1CC(OC(C)=O)C(n2cnc3cc(Cl)c(Cl)cc32)C1
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(OC(C)=O)C(n2c(Br)nc3cc(Cl)c(Cl)cc32)C1
Temperature: 70 °C

Procedure:
N-Bromosuccinimide (4.54 g, 25.5 mmol) was added to a solution of (±)-(1R*, 2R*, 4S*)-4-(acetoxymethyl)-2-(5,6-dichloro-1H-benzimidazol-1-yl)cyclopentyl acetate (8.95 g, 23.2 mmol) in dry N,N-dimethylformamide (46 mL). The solution was maintained at ca. 70° C. (oil bath) for 5 hours. Volatiles were removed in vacuo and the residual orange syrup chromatographed on silica gel. Title compound was eluted with chloroform as a pale yellow solid (5.14 g, 48%), m.p. 122°-125° C.; 1H-NMR (DMSO-d6)δ: 8.16 (s, 1, benzimidazole H7), 7.95 (s, 1, benzimidazole H4), 5.60-5.55 (m, 1, OCH), 5.12-5.03 (m, 1, NCH), 4.15 (d, J=6.3 Hz, 2, OCH2), 2.66-2.60 (m, 1, CHCH2), 2.29-2.14 (m, 3, CH), 2.06 (s, 3, CH3CO), 1.93 (s overlapped by m, 4, CH3CO+CH); mass spectrum (CI): 469 (5.8), 467 (37.5), 465 (95), 463 (54, M+1), 199 (100, M-B).
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.N([O-])=O.[Na+].[N-:18]=[N+:19]=[N-].[Na+]>FC(F)(F)C(O)=O.O>[N:1]([C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)=[N+:18]=[N-:19]
Reactant: COc1cc(N)c(I)cc1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(N=[N+]=[N-])c(I)cc1C(=O)O
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a solution of 4-amino-5-iodo-2-methoxybenzoic acid (300 mg, 1.02 mmol) in trifluoroacetic acid (4 ml) at 5° C., was added sodium nitrite (283 mg, 4.1 mmol) portionwise, and the mixture allowed to stir for 30 min. Sodium azide (200 mg, 3.07 mmol) was then added portionwise and the mixture stirred for a further 30 min at 0° C. The mixture was diluted with water, and a yellow solid precipithated. The solid was filtered, washed with cold water and dried, to afford the title compound (274 mg, 84%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])C(OC1C=CC=CC=1)=O)(=[O:15])=[O:14]>>[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3])(=[O:14])=[O:15]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Product: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccc(Cl)cc1)S(C)(=O)=O

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-chlorophenoxy)carbonyl]hydrazine (compound 10f) was prepared by reacting compound 2 with 4-chlorophenyl chloroformate using a procedure similar to that employed for compound 10d. The product was recrystallized from ethanol, and the yield was about 54.4% by weight. The Mp was approximately 124-125° C. 1H NMR (acetone-d6): δ 7.5 and 7.3 (4H, 2d, aromatic H), 3.9-4.2 (4H, m, CH2CH2Cl), 3.6 and 3.3 (6H, 2s, 2 CH3SO2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].[C:18](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:19]>>[CH3:17][C:3]1[C:2]([N:1]=[C:18]=[S:19])=[C:15]([CH3:16])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N
Product: Cc1ccc(CNC(=O)C(C)(C)C)c(C)c1N=C=S
Yield: 65 %

Procedure:
The title compound is prepared from N-(3-amino-2,4-dimethyl-benzyl)-2,2-dimethyl-propionamide, 1,1′-thiocarbonyldi-2-pyridone in analogy to step Af.
Reaction SMILES: O[N:2]1[CH:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:3]1.[ClH:23].[O:24]1CCOCC1>C(OCC)(=O)C>[ClH:23].[OH:24][CH:9]([CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH2:8][O:7][C:6]1[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:3][N:2]=1
Reactant: ON1OC(c2ccccc2)=CC1OCCCN1CCOCC1
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: OC(COc1cc(-c2ccccc2)on1)CN1CCOCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5.00 g of 3-(2-hydroxy-3-morpholinopropoxy-5-phenylisoxazole dissolved in ethyl acetate (200 ml) was added a 4N HCl/dioxane solution (5.0 ml) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to afford 5.21 g of the title compound with melting point 149°-150° C. as colorless powdery crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(N(C)C)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc([N+](=O)[O-])cc4)ccnc32)cc1
Temperature: 90 °C
Yield: 85.1 %

Procedure:
A 20 mL sealable tube under nitrogen was charged with 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in from Example 5, Step B), 1-fluoro-4-nitrobenzene (0.0786 g, 0.557 mmol), Cs2CO3 (0.272 g, 0.836 mmol), and DMA (4 mL). The reaction mixture was heated to 90° C. for 2 hours, then cooled to room temperature, diluted with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by Biotage 40S column eluting with Hexane/EtOAc 3:1, then EtOAc. Obtained the product (185 mg, 79%) as an off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.39 (d, J=5.1 Hz, 1H), 8.32 (d, J=9.4 Hz, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.26 (d, J=9.4 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 6.40 (d, J=5.5 Hz, 1H), 3.77 (s, 3H), 2.58 (s, 3H). LRMS (esi pos) m/e 391 (M+1).
Reaction SMILES: [ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][NH:19][C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[C:39]1([CH2:45][CH2:46]Br)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O>[ClH:1].[O:2]1[C@@H:14]2[C@@:15]34[CH2:17][CH2:18][N:19]([CH2:46][CH2:45][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C@@H:9]([C@:10]3([O:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:11][CH2:12][C:13]2=[O:20])[CH2:8][C:7]2=[C:16]4[C:3]1=[C:4]([O:31][CH3:32])[CH:5]=[CH:6]2
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)NCC[C@]314
Reactant: BrCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(OCCCc5ccccc5)[C@@H](C2)N(CCc2ccccc2)CC[C@]314
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A mixture of 4,5α-epoxy-3-methoxy-14β-(3-phenylpropyloxy)morphinan-6-one hydrochloride (1.0 g, 2.38 mmol), potassium carbonate (3.00 g, 21.7 mmol) and 2-phenylethylbromide (1.19 ml, 8.8 mmol) in water-free N,N-dimethylformamide (10 ml) was stirred for 12 h under exclusion of moisture and under nitrogen at 80° C. (bath temperature). After filtration from the inorganic residue, which was washed three times each time with 50 ml dichloromethane, the filtrate was evaporated down under reduced pressure. The oily residue was dissolved in 300 ml dichloromethane, washed with water (3×200 ml) and saturated sodium chloride solution (4×200 ml), dried over sodium sulphate and evaporated down. The evaporation residue (960 mg of brown oil) was purified by column chromatography (silica gel; CH2Cl2/MeOH/conc. NH4OH 250:2:0.5), the oily evaporation residue dissolved in 50 ml ether and precipitated by the addition of etherial HCl up to the acidic reaction. Yield: 0.45 g (36%) of the compound 4.HCl as colourless crystals. Fp. 128-130° C.; MS (CI): 524 (M++1); IR (KBr): 1726 (C═O) cm−1; 1H-NMR (DMSO-d6, δ in ppm): δ 8.84 (s, wide, HN+), 7.39-7.17 (m, 10 arom. H), 6.89 (d, 1 arom. H, J=8.2 Hz), 6.79 (d, 1 arom. H, J=8.2 Hz), 4.95 (s, CH-5), 3.81 (s, CH3O).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH:21]=O)=[CH:15][CH:14]=1>>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]2[NH:1][C:2]3[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[O:10])[C:3]=3[CH:21]([C:20]3[CH:23]=[CH:24][CH:25]=[C:18]([O:17][C:16]4[CH:26]=[CH:27][C:13]([O:12][CH3:11])=[CH:14][CH:15]=4)[CH:19]=3)[C:3]=2[C:4](=[O:10])[CH2:5]1
Reactant: CC1(C)CC(=O)C=C(N)C1
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Product: COc1ccc(Oc2cccc(C3C4=C(CC(C)(C)CC4=O)NC4=C3C(=O)CC(C)(C)C4)c2)cc1

Procedure:
3-Amino-5,5-dimethyl-2-cyclohexen-1-one was reacted with 3-(4-methoxyphenoxy)-benzaldehyde in an analogous manner to that described in Example 1 to give 3,4,6,7,9,10-hexahydro-3,3,6,6-tetramethyl-9-[3-(4-methoxyphenoxy)-phenyl]-1,8(2H,5H)-acridinedione. Crystallization from ethanol/water gave a pale yellow crystalline solid of melting point 210-212° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:10]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][N:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:29](=[O:31])[CH3:30])[C:10]=1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCNCc1nc2ccccc2c(OCc2ccccc2)c1C
Solvent: c1ccncc1
Product: CCCCCCCN(Cc1nc2ccccc2c(OCc2ccccc2)c1C)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N-{[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}heptane-1-amine (153 mg) in pyridine (5 mL) was added acetic anhydride (0.06 mL), followed by stirring at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and water (10 mL) and 1M hydrochloric acid (10 mL) were added to the residue, followed by extraction with ethyl acetate (50 mL). The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain N-{[4-(benzyloxy)-3-methylquinolin-2-yl]methyl}-N-heptylacetamide (158 mg).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([NH:10][C:11](=[O:31])[C@H:12]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:13][C:14](=[O:26])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][O:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][CH:5]1[CH:9]([NH:10][C:11](=[O:31])[C@H:12]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH:13][C:14](=[O:26])[NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][O:6]1
Reactant: CC(=O)O[C@@H]1OCC[C@@H]1NC(=O)[C@H](CC(C)C)NC(=O)Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)Nc1cccc2ccccc12)C(=O)NC1CCOC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
(2S,3S)-2-Acetoxy-3-[[N-(1-naphthylcarbamoyl)-(L)-leucyl]amino]tetrahydrofuran (2.9 g) was suspended in methanol (50 ml) followed by addition of a solution of potassium carbonate (0.94 g) in water (5 ml) under ice-cooling and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4) and the solvent was distilled off to give 2-hydroxy-3-[[N-(1-naphthylcarbamoyl)-(L)-leucyl]amino]tetrahydrofuran (chemical formula below) (1.95 g, 72%). As recrystallized from dichloromethane-methanolisopropyl ether, colorless crystals, m.p. 177°-178° C., optical rotation [α]D +29.5° (c=0.25, dimethyl sulfoxide).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([CH:18]=[O:19])=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:23]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([N:8]1[C:16]2[CH:15]=[C:14]([Cl:17])[N:13]=[CH:12][C:11]=2[C:10]([C:18]([OH:23])=[O:19])=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: CC(C)c1c(C=O)c2cnc(Cl)cc2n1Cc1ccccc1
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)c1c(C(=O)O)c2cnc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-benzyl-6-chloro-2-isopropyl-1H-pyrrolo[3,2-c]pyridine-3-carbaldehyde (Compound 14, 146 mg, 0.47 mmol) in t-BuOH (15 ml) and 2-methyl-2-butene (10 ml) was added a solution of NaH2PO4 (1.41 g, 11.8 mmol) and NaClO2 (80%, 1.05 g, 9.3 mmol) in H2O (10 ml). The mixture was stirred at room temperature for 16 h and was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes, then 0→30% MeOH—CH2Cl2) to yield the title compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[CH:3][N:2]([CH3:5])[CH3:1])[CH:19]=[O:20]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
73 g of dimethylformamide are cooled to -50° C. 92 g of phosphorus oxychloride are added dropwise, followed by 34.2 g of 2-chlorophenylacetic acid, and the reaction mixture is stirred at room temperature for 30 minutes. It is then heated at 70°-80° C. for 5 hours 30 minutes. The reaction mixture is rendered alkaline with potassium carbonate, 200 ml of toluene are added and the mixture is heated in a water bath for 1 hour.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:18][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]2[CH:5]=[N:4][C:3]([CH:2]=[O:1])=[C:7]2[CH2:8]1
Reactant: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CN1Cc2c(C=O)ncn2-c2ccccc2C1=O

Procedure:
6.73 g (27.6 mmol) of 4,5-dihydro-3-hydroxymethyl-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature for 4 hours together with 33 g (380 mmol) of manganese dioxide in 100 ml of methylene chloride. The mixture was filtered, the filter residue was rinsed thoroughly with about 1.5 l of methylene chloride and the filtrate was evaporated. There was obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3--carboxaldehyde of melting point 202°-203°.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:28])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([Cl:28])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccccc4)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cc(Cl)cc(-c3ccccc3)c2O1
Yield: 92.1 %

Procedure:
Treatment of (±)-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.55 g, 1.33 mmol) with sodium azide (0.345 g, 5.31 mmol) generally according to the procedure described for Intermediate 98 provided 0.35 g of (±)-2-(azidomethyl)-5-chloro-7-phenyl-2,3-dihydro-1-benzofuran as a colorless oil. Treatment of the azide with sulfided platinum on carbon (90 mg, 5 wt. %) generally according to the procedure described for Example 1 provided 0.14 g (40%) of (±)-1-(5-chloro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 258° C. (dec); Anal. calcd. for C15H14ClNOHCl: C, 60.83; H, 5.1; N, 4.73. Found: C, 60.13; H, 4.95; N, 4.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Br[CH:13]([CH:20]=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(Br)C=O
Reactant: COc1ccc(C(N)=S)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)Cc1cnc(-c2ccc(OC)cc2)s1
Yield: 66.5 %

Procedure:
4-Methoxythiobenzamide (1.62 g, 9.7 mmol) and ethyl 3-bromo-4-oxobutanoate (2.02 g, 9.7 mmol) were suspended in 1,2-dichloroethane (25 ml), and the mixture was heated under reflux for 3 hours. The reaction mixture was diluted with ethyl acetate, successively washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give ethyl [2-(4-methoxyphenyl)-1,3-thiazol-5-yl]acetate (1.79 g, yield: 67%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:32]([O:33][CH2:34][CH:35]([F:37])[F:36])=[CH:31][C:9]2[N:10]([CH3:30])[C:11]([NH:13][C:14]3[CH:19]=[C:18]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:17]=[CH:16][C:15]=3[Cl:29])=[N:12][C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[Cl:29][C:15]1[CH:16]=[CH:17][C:18]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][C:14]=1[NH:13][C:11]1[N:10]([CH3:30])[C:9]2[CH:31]=[C:32]([O:33][CH2:34][CH:35]([F:37])[F:36])[C:6]([C:4]([OH:5])=[O:3])=[CH:7][C:8]=2[N:12]=1
Reactant: CCOC(=O)c1cc2nc(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Cl)n(C)c2cc1OCC(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(C(=O)O)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A mixture of ethyl-2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylate (1.35 g; 2.50 mmol), NaOH (4 mL; 2 M aq; 8 mmol) and 1,4-dioxane (15 mL) was refluxed for 3 h. After cooling to rt the mixture was acidified to pH ˜5-6 and extracted with EtOAc. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O to give the sub-title compound. Yield: 1.12 g (88%).