Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:23]([C:24]#[N:25])=[CH:22][C:8]2[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])=[N:10][CH2:11][C:12](=[O:14])[NH:13][C:7]=2[CH:6]=1.[CH3:26][O:27][CH2:28][CH2:29][N:30](C)[CH2:31]CO.[I-].[Na+]>O1CCCC1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[C:8]2[CH:22]=[C:23]([C:24]#[N:25])[C:5]([O:4][CH2:3][CH2:2][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])=[CH:6][C:7]=2[NH:13][C:12](=[O:14])[CH2:11][N:10]=1
Reactant: COCCN(C)CCO
Reactant: N#Cc1cc2c(cc1OCCCl)NC(=O)CN=C2c1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=O)N2
Temperature: 83 °C
Yield: 17.1 %

Procedure:
A mixture of 1.2 g (0.0032 mole) of 8-(2-chloroethoxy)-5-(2-chlorophenyl)-7-cyano-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Iss, prepared in Example 35), 2.85 g (0.032 mole) of 2-((2-methoxyethyl)methylamino) ethanol, 20 mL of tetrahydrofuran and 4.8 g (0.032 mole) of sodium iodide was heated in an oil bath at 83° C. under an argon atmosphere for 20 hours. The mixture was cooled and then partitioned between ethyl acetate and 0.6 M sodium bicarbonate solution. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with acetonitrile-methanol (80:20) to give 0.233 g of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-2H-1,4-benzodiazepin-2-one (Iv).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][CH2:38][O:39][CH2:40][C@H:41]([O:52][C:53]1[N:58]=[CH:57][N:56]=[C:55]2[N:59]([C:62]3[CH:67]=[C:66]([F:68])[CH:65]=[CH:64][C:63]=3[CH3:69])[N:60]=[CH:61][C:54]=12)[C:42]([NH:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][N:46]=1)=[O:43])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[Cl:51][C:48]1[CH:49]=[CH:50][C:45]([NH:44][C:42](=[O:43])[C@@H:41]([O:52][C:53]2[N:58]=[CH:57][N:56]=[C:55]3[N:59]([C:62]4[CH:67]=[C:66]([F:68])[CH:65]=[CH:64][C:63]=4[CH3:69])[N:60]=[CH:61][C:54]=23)[CH2:40][O:39][CH2:38][CH2:37][OH:36])=[N:46][CH:47]=1
Reactant: Cc1ccc(F)cc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1-n1ncc2c(O[C@@H](COCCO)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.538 mL, 0.54 mmol) was added to (2S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-chloropyridin-2-yl)-2-(1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (Intermediate AK5) (390 mg, 0.54 mmol) in THF (5 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated NH4Cl (2 mL), diluted with DCM (25 mL) and poured onto a phase separator. The organic phase was evaporated to give the crude product. This was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents to afford the product (136 mg, 51.9%, 75% ee). 1H NMR (400 MHz, DMSO) δ 1.88 (3H, s), 3.35 (2H, m), 3.43 (2H, m), 3.84 (1H, dd), 3.92 (1H, dd), 4.47 (1H, t), 5.74 (1H, m), 7.19 (2H, m), 7.36-7.29 (1H, m), 7.71 (1H, dd), 7.83 (1H, d), 8.23 (1H, d), 8.37 (1H, s), 8.43 (1H, s), 11.05 (1H, s). m/z (ES+) (M+H)+=487; HPLC tR=2.28 min.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH2:27][NH2:28])[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:28]([CH2:27][C:19]2[CH:20]=[C:21]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:22]=[C:17]([Cl:16])[CH:18]=2)[CH:10]=1
Reactant: CS(=O)(=O)c1cc(Cl)cc(CN)c1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CS(=O)(=O)c1cc(Cl)cc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Yield: 42.9 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.68 g), 1-[3-chloro-5-(methylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 3 (2.2 g) and potassium carbonate (2.97 g) were stirred in ethanol (30 ml) at 85° C. for 24 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (3 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.63 g).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C@H:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1>[Pd].CO>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C@H:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Reaction time: 3 h
Yield: 35.5 %

Procedure:
Palladium on carbon (11.8 mg; 10% Pd/C) was added to a solution of tert-butyl (4S)-4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)azepane-1-carboxylate (49.7 mg, 0.33 mmol) in methanol (1.5 mL) and the resulting mixture was stirred under hydrogen (balloon) for 3 hours. TLC analysis showed the reaction was complete. The reaction mixture was filtered through a microfilter and the filtrate was concentrated under vacuum to afford the impure title compound as a white foam (44.8 mg) which was used without purification in the next step.
Reaction SMILES: C(N)C.[C:4]([NH:7][C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=1)[C:9]([OH:11])=[O:10])(=[O:6])[CH3:5]>CO.C1CC=CCCC=C1.C1CC=CCCC=C1.C(F)(F)(F)S([O-])(=O)=O.[Rh]>[C:4]([NH:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Br:20])[CH:14]=1)[C:9]([OH:11])=[O:10])(=[O:6])[CH3:5]
Reactant: CC(=O)NC(=Cc1ccc(F)c(Br)c1)C(=O)O
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: CCN
Solvent: C1=CCCC=CCC1
Solvent: CO
Product: CC(=O)N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A mixture of bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate (0.11 g, 0.18 mmol) and (R)—N-diphenylphosphino-N-methyl-1-[(S)-2-diphenylphosphino)ferrocenyl]ethylamine [(R)-methyl BoPhoz; 70 mg, 0.15 mmol] in MeOH (150 mL) under N2 was stirred for 30 min. 2-Acetylamino-3-(3-bromo-4-fluoro-phenyl)-acrylic acid (4.5 g, 15 mmol) was added, and the mixture was stirred under H2 (40 psi) on a Parr apparatus for 18 h. The mixture was concentrated to give the title compound as an orange oil (4.5 g, 100%). MS (ESI−): mass calcd. for C11H11BrFNO3, 303.0; m/z found, 301.8 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 7.50 (dd, J=6.7, 2.1, 1H), 7.24 (ddd, J=8.4, 4.7, 2.2, 1H), 7.13 (t, J=8.6, 1H), 4.65 (dd, J=9.0, 5.2, 1H), 3.19 (dd, J=14.0, 5.2, 1H), 2.93 (dd, J=14.0, 9.0, 1H), 1.93 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.[NH2:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18].O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][S:18]1
Reactant: O=C(c1ccccn1)c1ccccn1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Solvent: O
Product: O=C(O)C1CSC(c2ccccn2)(c2ccccn2)N1
Yield: 11 %

Procedure:
A mixture of 3.68 g of di-2-pyridyl ketone, 2.42 g of L-cysteine, 25 ml of water and 25 ml of ethanol was refluxed for 3.5 hours. After allowing the mixture to cool, the insoluble matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed in sequence with ethyl acetate and ether to give 0.63 g of 2,2-di(2-pyridyl)thiazolidine-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1.[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)=[O:21].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:9])=[N:6][CH:7]=1)=[O:21]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc(-c2ccccc2C=O)cn1
Temperature: 25 °C

Procedure:
tert-Butyl 3-(5-bromopicolinamido)propanoate (1.0 g, 3.0 mmol), 2-formylphenylboronic acid (547 mg, 3.6 mmol), Pd(dppf)Cl2 (249 mg, 0.3 mmol), and K2CO3 (840 mg, 6.1 mmol) were dissolved in 1,4-dioxane (20 mL) and water (5 mL) and heated to 80° C. After 3 h the resulting mixture was cooled to room temperature, diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: C(=O)(O[CH:5]1[CH:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6]1)OC.[C:28]1([S:34]([CH2:37][N+:38]([O-:40])=[O:39])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1COCC1.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>[N+:38]([CH:37]([CH:5]1[CH:9]([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:8]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:7]=[CH:6]1)[S:34]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:36])=[O:35])([O-:40])=[O:39]
Reactant: O=[N+]([O-])CS(=O)(=O)c1ccccc1
Reactant: COC(=O)OC1C=CC(OCc2ccccc2)C1COCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])C(C1C=CC(OCc2ccccc2)C1COCc1ccccc1)S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.6 %

Procedure:
To a round bottomed flask equipped with an argon inlet, a magnetic stirrer and a cooling bath was dissolved crude 10 (9.8 g, 26.5 mmol), phenylsulfonylnitromethane (5.4 g, 26.8 mmol) and tetrakis(triphenylphosphine)palladium (0.6 g, 0.52 mmol) in THF (80 mL) at 0° C. The reaction mixture was degassed using argon for a few minutes. Triethylamine (8.4 g, 11.1 mL, 79.5 mmol) was added to the reaction mixture over the course of 10 minutes at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then quenched with 2 N HCl at 0° C. (100 mL) and extracted with hexane/ethyl acetate (1:1; 2×30 mL). The combined organic layer was washed with brine (100 mL), dried (sodium sulfate), and concentrated in vacuo to afford a red-colored oily residue. Silica pad filtration was conducted using ethyl acetate to remove the baseline materials and give the title compound (14.2 g crude, >100%) as a light brown oil which was used in the next step without any further purification.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25](Br)=[C:24]([CH3:30])[CH:23]=2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[C:36]([CH3:43])[CH:35]=1>>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:25]2[C:26]([CH3:28])=[CH:27][C:22]([O:21][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:23][C:24]=2[CH3:30])=[C:36]([CH3:43])[CH:35]=1
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCCCCC(Oc1cc(C)c(-c2ccc(F)cc2C)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-heptyl]-benzoylamino}-propionic acid methyl ester and 4-fluoro-2-methyl-phenylboronic acid as starting materials in step D. MS (ES): 520.2 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:26]=[CH:25]C(N)=[CH:22][CH:21]=1.Cl>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Reactant: Nc1ccc(F)cc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CNc1ccc(F)cc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.4 ml (118 mmol) of 4-fluoroaniline were dissolved in 200 ml of isopropanol at 40° C. The solution was admixed with 3.6 ml (43.5 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 30 min. The suspension was cooled to 10° C. and the crystallized product was filtered off. Yield: 12.4 g (94% of theory) 1H NMR: 3.62 (s, 3H); 7.05-7.24 (m, 4H); 7.48-7.52 (m, 3H); 7.88 (d, 1H); 8.00-8.04 (m, 2H); 8.90 (d, 1H); 9.15 (s, 1H)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[O:20][CH3:21]>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:11][CH:1]=[O:3])=[C:13]([O:20][CH3:21])[CH:14]=1)#[N:17]
Reactant: COc1cc(C#N)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COc1cc(C#N)ccc1NC=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Acetic anhydride (0.65 mL, 6.7 mmol) was cooled in an ice bath and formic acid (0.38 mL, 10 mmol) was added with stirring. The ice-bath was removed and the mixture was stirred for a further 60 minutes. The reaction was re-cooled in the ice-bath and 4-amino-3-methoxybenzonitrile (0.25 g, 1.58 mmol) was added. The reaction was stirred at ice-bath temperature for 5 minutes, then at room temperature for 60 minutes. The reaction was concentrated in vacuo, azeotroped with toluene and the title compound was precipitated from ether/hexanes as a white powder (255 mg, 71.3%).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.OCC(=O)C.[NH3:24].[OH-].[Na+]>O>[NH2:24][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Reactant: N
Agent: CC(=O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
70 ml of water, 26.5 g of 1,4-dihydroxyanthraquinone, 1.2 g of hydroxyacetone, 80 g of 25% strength by weight aqueous ammonia solution and 20 g of 50% strength by weight sodium hydroxide solution were introduced into a pressure-resistant apparatus. The apparatus was then sealed pressure-tight and its contents were heated to 100° C., giving rise to an autogenous pressure of 2.7 bar. The reaction mixture was held under these conditions for 3 h, then cooled down and depressurized. The precipitate found was filtered off with suction, washed salt-free with water and dried to leave 15.8 g of 1-amino-4-hydroxyanthraquinone (purity according to GC: 71.1%).
Reaction SMILES: C([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6](OCC)=O)(=O)C.BrC[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>[O-]CC>[NH2:4][CH:5]([CH2:6][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOC(=O)CCCCCCBr
Agent: CC[O-]
Agent: Cl
Product: CCOC(=O)CCCCCCC(N)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Diethyl acetamidomalonate (16.7 g) and ethyl 7-bromoheptanoate (16.6 g) were dissolved in ethanolic ethoxide (prepared from sodium (1.51 g) and absolute ethanol (30 ml)) and the mixture was refluxed for 27 hours. The cooled solution was poured into ice-water, the product was extracted into ether, and the dried extract was evaporated to give crude diethyl acetamido-(6-ethoxycarbonylhexyl) malonate as a pale yellow oil, δ2.2(3H, singlet, --COCH3), 4.17(6H, multiplet, 3×--OCH2 --CH3). This amide was refluxed with concentrated hydrochloric acid (111 ml) for 51/2 hours, the cooled solution was washed with ether, and the aqueous layer was decolorised with activated charcoal and evaporated to dryness in vacuo. The residual colourless glass was dissolved in the minimum quantity of absolute ethanol and added dropwise to a stirred, cooled (-10° C.) mixture of absolute ethanol (125 ml) and thionyl chloride (15.7 g). The resulting solution was set aside at room temperature for 1 hour, refluxed for 11/2 hours, cooled, and poured into ice-water, adjusting the pH to 9 with aqueous sodium hydroxide. The mixture was extracted with ether, and the dried extract was concentrated and distilled, giving diethyl 2-aminononanedioate (55% yield) as a colourless oil, b.p. 114°-115°/0.02-0.03 mm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][CH:36]=[N:35]2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cccn2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and 3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionic acid tert.-butyl ester (Example K16) according to the general procedure M. Obtained as a light yellow solid (135 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([CH2:20][S:21][C:22]2[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Cc1c(SCCCNCc2ccccc2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CCCSc1ccnc(CSc2nc3ccccc3[nH]2)c1C)Cc1ccccc1
Reaction time: 1 h

Procedure:
2-((3-Methyl-4-(3-benzylaminopropylthio)-2-pyridyl)methylthio)-1H-benzimidazole (2.0 g) was dissolved in dimethylformamide (25 ml) and thereto were added ethyl bromoacetate (0.834 g) and potassium carbonate (0.984 g). The mixture was stirred at 40°-50° C. for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure. The residue was subjected to column chromatography and eluted with chloroform-methanol to give 2-((3-methyl-4-(3-(N-benzyl-N-ethoxycarbonylmethylamino)propylthio)-2-pyridyl)methylthio)-1H-benzimidazole.
Reaction SMILES: [CH:1]1[N:5]2[C:6]3[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=3[CH2:8][CH2:9][C@@H:10]([NH:11][C:12]([C:14]3([NH:17]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)=[O:13])[C:4]2=[N:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:14]1([C:12]([NH:11][C@@H:10]2[CH2:9][CH2:8][C:7]3[CH:25]=[CH:26][CH:27]=[CH:28][C:6]=3[N:5]3[CH:1]=[CH:2][N:3]=[C:4]23)=[O:13])[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(C(=O)N[C@@H]2CCc3ccccc3-n3ccnc32)CC1
Yield: 74.3 %

Procedure:
Dissolve tert-butyl N-[1-[[(4R)-5,6-dihydro-4H-imidazo[1,2-a][1]benzazepin-4-yl]carbamoyl]cyclopropyl]carbamate (856 mg, 2.24 mmol) in dichloromethane (20 mL) and cool in an ice bath. Add trifluoroacetic acid (10 mL, 132.25 mmol). Remove the bath and stir the reaction for 1 hr. Concentrate the mixture under reduced pressure and add ethyl acetate. Wash with 1N NaOH and brine, dry over sodium sulfate, and concentrate the organic layer under reduced pressure to give the title compound (470 mg, 74%) as a white solid: MS (m/z): 283 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](Cl)=[O:11].C(N(CC)CC)C.[OH:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:11]
Reactant: Oc1cccnc1
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Oc1cccnc1)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a stirred solution of 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoyl chloride (3.79 g, 0.01 mole) and triethyl amine (1.01 g, 0.01 mole) in toluene (50 ml) was added 3-hydroxypyridine (0.95 g, 0.01 mole). The temperature exothermed to 33° C. and there was an immediate precipitate. The reaction was then refluxed for 24 hours, cooled to room temperature and the triethylamine hydrochloride precipitate collected by filtration. The toluene solution was washed with dilute sodium hydroxide solution and then with saturated sodium chloride solution. After drying and evaporation of the solvent there was obtained 3.1 g of brown oil which solidified. This was triturated with hexane and the solid filtered and dried to give a tan product, m.p. 65°-68° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[CH:4]=1)#[N:2].[NH4+].[OH-:28].OO>>[C:1]([C:3]1[C:12]2=[CH:13][N:14]([C@@H:16]3[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@@:17]3([CH3:25])[OH:18])[N:15]=[C:10]3[C:11]2=[C:5]([C:6](=[O:26])[NH:7][N:8]=[CH:9]3)[CH:4]=1)(=[O:28])[NH2:2]
Reactant: [OH-]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(C#N)cc3c(=O)[nH]ncc(n1)c23
Agent: OO
Agent: [NH4+]
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2c(C(N)=O)cc3c(=O)[nH]ncc(n1)c23

Procedure:
To the compound from Example 24 is added a NH4OH and H2O2 in alcoholic solution to yield the titled compound.