Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][N:19]=1>C(O)(=O)C>[CH3:4][N:5]([CH2:7][C:12]1[O:8][C:9]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[O:27][C:28]([CH2:7][N:5]([CH3:4])[CH3:6])=[CH:29][CH:30]=3)=[CH:20][N:19]=2)=[CH:10][CH:11]=1)[CH3:6]
Reactant: O=c1[nH]c(NCCSCc2ccco2)ncc1Cc1ccco1
Reactant: CN(C)CN(C)C
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)o3)c(=O)[nH]2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bis-dimethylaminomethane (1.23 g,) was added whilst stirring 2-[2-(2-furanylmethylthio)ethylamino]-5-(2-furanylmethyl)-4-pyrimidone (0.8 g) was suspended in glacial acetic acid (8 ml). The mixture was then stirred at room temperature for 3 hr and allowed to stand for ca 16 hr. The acid was evaporated at reduced pressure azeotropically with water. The residual oil was dissolved in water, filtered and the filtrate taken to pH 9 using aqueous sodium carbonate solution. The basic solution was extracted using ethyl acetate, the extracts dried (MgSO4) and evaporated to give 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone as an oily residue (1.01 g). The oily residue was dissolved in a minimum volume of ethanol and then acidified with ethanolic hydrochloric acid. The acidic solution was then evaporated to dryness and the residual oil was crystallised from isopropanol/ethanol to give the white solid trihydrochloride salt (1.33 g) m.p. 177°-9° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+].F[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1)[CH:2]=[CH2:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: C=CCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Oc2ccc(C=O)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
The crude product from Example 61B in anhydrous DMF (40 mL) was treated with K2CO3 (15.5 g, 112 mmoles) and 4-fluorobenzaldehyde (4.82 mL, 44.9 mmoles). The reaction mixture was stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate. The mixture was washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 8% ethyl acetate:hexanes) to provide the title compound (5.75 g, 60%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@@H:9]1[C:21](=[O:35])[NH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:33])[N:30]([CH3:32])[CH3:31])=[CH:25][C:24]=1[F:34])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:31][N:30]([CH3:32])[C:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:21]([C@H:9]2[CH2:10][C@@H:11]([OH:13])[CH2:12][NH:8]2)=[O:35])=[C:24]([F:34])[CH:25]=1)=[O:33]
Reactant: CN(C)C(=O)c1ccc(NC(=O)[C@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(NC(=O)[C@H]2C[C@@H](O)CN2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Into a solution of 6 (0.33 g, 0.647 mmol) in anhydrous CH2Cl2 (10 mL) was added TFA (2 mL). The solution was stirred at RT for 4 h before concentrating under reduced pressure to give 7 (0.19 g, 100%).
Reaction SMILES: C=O.Cl.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[OH:18])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1.[C:22](O)(=O)C.C([BH3-])#N.[Na+]>O>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][N:15]([CH3:22])[CH2:14][C@H:13]2[OH:18])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1CCNC[C@H]1O
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: O
Product: CN1CC[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Add formaldehyde (20.5 mL, 37-41% aqueous solution) to a solution of (3R,4R)-4-(4-bromo-2-nitro-phenylamino)-piperidin-3-ol.hydrochloride salt (0.0.024 mol, 8.68 g) and acetic acid (10.2 mL) in water (42 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.073 mol, 4.6 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (7.8 g, 97%). 1H NMR (400 MHz, CDCl3) δ 1.63-1.71 (m, 1H), 2.16-2.21 (m, 2H), 2.33 (s, 3H), 2.35-2.38 (m, 1H), 2.60 (br s, 1H), 2.80 (d, 1H), 3.54-3.56 (m, 1H), 3.75-3.79 (m, 1H), 6.92 (d, 1H), 7.48 (dd, 1H), 8.14 (d, 1H), 8.30 (d, 1H).
Reaction SMILES: N#N.I[C:4]1[C:5]([OH:13])=[N:6][CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[S:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C([O-])(=O)C.[K+]>CN(C=O)C.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+:10]([C:8]1[CH:9]=[C:4]([C:18]2[S:14][CH:15]=[N:16][CH:17]=2)[C:5]([OH:13])=[N:6][CH:7]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cnc(O)c(I)c1
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(O)c(-c2cncs2)c1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
N2 was bubbled through a solution of 3-iodo-5-nitropyridin-2-ol (1.33 g, 5.00 mmol), thiazole (2.13 g, 25.0 mmol), potassium acetate (1.47 g, 15.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.4 g, 0.4 mmol) in DMF (10 mL) for 10 min. The mixture was then heated to 120° C. and stirred for 17 h. The solvents were removed in vacuo. The residue was stirred with methanol (5 mL) and dichloromethane (10 mL) for 30 min. The solids were collected by filtration, washed with dichloromethane (2 mL) and water (3×8 mL), and dried in vacuo to afford the title compound as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz): δ=8.74 (d, J=2.8 Hz, 1H), 8.77 (s, 1H), 8.79 (d, J=2.8 Hz, 1H), 9.12 (s, 1H), 13.26 (s, br, 1H). MS (ES+): m/z 224.09 [MH+]. HPLC: tR=2.16 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].CC1C=CC(S(O[CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=2)(=O)=O)=CC=1>>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][N:17]2[CH2:18][CH2:19][N:14]([C:13]3[C:7]4[O:6][C:5]([C:3]([N:2]([CH3:20])[CH3:1])=[O:4])=[CH:9][C:8]=4[CH:10]=[CH:11][CH:12]=3)[CH2:15][CH2:16]2)=[N:35][CH:36]=1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCNCC3)c2o1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cn2)cc1
Product: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4ccc(F)cn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 46 starting from N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.085 g, 0.31 mmol) (Example 39d) and 2-(5-fluoropyridin-2-yl)ethyl 4-methylbenzenesulfonate (0.092 g, 0.31 mmol). The product was purified by preparative HPLC to give the title compound. Yield: 0.049 g (39%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[C:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)#[N:8].C(N(CC)CC)C>ClCCl>[C:7]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[O:14])=[CH:11][CH:10]=1)#[N:8]
Reactant: NCCCCO
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)NCCCCO)cc1
Temperature: 5 °C
Reaction time: 15 h

Procedure:
100 mmol (9.2 ml) of 4-aminobutanol are slowly added, at a temperature of 5° C., to 100 mmol (16.56 g) of 4-cyanobenzoyl chloride in 400 ml of dichloromethane. While maintaining the temperature at 5° C., 100 mmol (13.9 ml) of triethylamine are added. The reaction mixture is stirred for 15 hours at room temperature before being hydrolysed. The organic phase is then decanted off and washed with a 1N hydrochloric acid solution. After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel using a 97/3 dichloromethane/methanol mixture as eluant to yield the expected product.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][C:13](=[O:15])[CH3:14].[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][CH:13]([OH:15])[CH3:14]
Reactant: CC(=O)Cc1c(C)ccc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc2ccccc2c1CC(C)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
1-(2-Methyl-naphthalen-1-yl)-propan-2-one (1.14 g, 5.76 mmol) was dissolved in Et2O (30 mL) in an argon-purged, round-bottom flask. The mixture was chilled to −78° C. and LiAlH4 (438 mg, 11.52 mmol) was added. The reaction was stirred at −78° C. for five minutes and then at room temperature for twenty minutes. TLC analysis (silica, 20% EtOAc-hexanes) indicated the reaction was complete. The reaction was chilled again to −78° C. and was carefully quenched with saturated aqueous KHSO4 (˜2 mL). The mixture was warmed to room temperature, diluted with H2O, and extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, filtered through celite, and concentrated to give 1-(2-methyl-naphthalen-1-yl)-propan-2-ol in quantitative yield. MS (APCI) m/z 200.2 (M−H).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:14]=2[C:15]#[N:16])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH:10]([OH:24])[CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([NH2:21])[C:14]=2[C:15]#[N:16])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2cccc([N+](=O)[O-])c2C#N)ccc(C(C)=O)c1O
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCCc1c(OCC(O)COc2cccc(N)c2C#N)ccc(C(C)=O)c1O
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A solution of 10 g of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-6-nitrobenzonitrile, 2.5 g 10% Pd on carbon and 10 g cyclohexene in 500 ml absolute ethanol is refluxed for 30 min. The reaction mixture is cooled to room temperature, filtered through Celite and freed of solvent. Trituration with diethyl ether and drying of the insolubles gives 6.1 g of the title compound as a white solid, m.p. 123°-125° C.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1(=[O:24])[O:23][CH2:22][CH2:21]1.Cl>[OH-].[Na+]>[OH:18][CH:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:22][CH2:21][C:20]([OH:24])=[O:23])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: O=C1CCO1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1(C2CCCC2)Cc2cc(OCCC(=O)O)c(Cl)c(Cl)c2C1O

Procedure:
2-Cyclopentyl-2-methyl-6,7-dichloroindan-1,5-diol (Example 5, Step C) (15.6 g., 0.05 mole) is dissolved in a 10% sodium hydroxide solution (50 ml.). The solution is heated to reflux and beta-propiolactone, (36.0 g., 0.5 mole) is added at such as to keep the reaction mixture refluxing. The reaction mixture is kept basic by the addition of 10% sodium hydroxide. The reaction mixture is cooled and acidified with dilute hydrochloric acid. The product is extracted with ether and extracted from the other solution with a 5% solution of sodium bicarbonate. Acidification affords the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6])=[O:2].[CH:12]([N:15](CC)[CH:16](C)C)(C)C.CNC.C(O)C>ClCCl.C(OCC)C>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:15]([CH3:16])[CH3:12])=[O:6])=[O:2]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: CN(C)C(=O)c1ccccc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 2-formylbenzoic acid (500 mg, 3.33 mmol), N,N-diisopropylethylamine (0.58 mL, 3.3 mmol), and dimethylamine/ethanol solution (1.2 mL, 5.6 M, 6.7 mmol) in 3.3 mL of dichloromethane was added 1-ethyl-3-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (1.28 g, 6.67 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with diethyl ether. The solution was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain the title compound as a pale yellow oil (113 mg, 19%).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]([OH:13])=[O:12])[C:4]1=[O:14].O=[C:16]([CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18].C([BH3-])#N.[Na+]>C(N(CC)CC)C>[C:11]([CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:3]([NH:2][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:4]1=[O:14])([OH:13])=[O:12]
Reactant: CCOC(=O)C(=O)CCCc1ccccc1
Reactant: N[C@H]1CCCCN(CC(=O)O)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCCc1ccccc1)N[C@H]1CCCCN(CC(=O)O)C1=O

Procedure:
React 1.08 g 3-(S)-amino-1-carboxymethylperhydroazepin-2-one hydrochloride, 5.3 g ethyl 2-oxo-5-phenylpentanoate, 0.49 g triethylamine and 630 mg sodium cyanoborohydride as described in Example 2. Purify the crude product by chromatography on LH 20 and isolate the desired ester.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:5]=[N:6][C:7]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1.O.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:4]1[N:5]=[N:6][C:7]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)CCNc1ccc(Cl)nn1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCNc1ccc(OCc2ccccc2)nn1
Temperature: 180 °C
Yield: 47 %

Procedure:
Sodium hydride (22.0 mmol, 0.88 g) was dissolved in benzyl alcohol (10 mL). To the resulting solution was added N-(3-chloropyridazin-6-yl)-3-aminopropionic acid (10.0 mmol, 2.01 g), and the mixture was heated to about 165° C. (oil bath 180° C.) for 3 hours. After cooling to room temperature, water (120 mL) was added, and the aqueous phase was extracted with dichloromethane (3×50 mL). The pH was adjusted to 4.0 with 2M aqueous hydrochloric acid. The light brown precipitate was filtered, washed with water (2×1 mL) and dried over phosphorus pentoxide. The resulting solid was dried to give 1.36 g (47%) of the title compound. The product was pure according to TLC Rf 0.16 (dichloromethane/methanol/acetic acid, 85:10:5).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]O)[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:27]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28]>C(Cl)Cl>[C:11]([N:18]1[CH2:19][CH2:20][CH:21]([CH2:24]/[CH:25]=[CH:32]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:23]1)([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
To a stirred solution of oxalyl chloride (0.43 mL, 5.0 mmol) in CH2Cl2 (30 mL) at −78° C. is added DMSO (0.52 mL, 7.0 mmol) dropwise. After gas evolution subsided (5 min), the alcohol of Example 4 (0.8 g, 3.5 mmol) in CH2Cl2 (20 mL) is added in a stream. After 20 min, (carbethoxymethylene) triphenyl-phosphorane (1.4 g, 4.0 mmol) is added. After 2 h, the reaction mixture is diluted with petroleum ether, washed with water, 5% KHSO4 and sat. NaCl, dried over MgSO4, and concentrated. Flash column chromatography (15% EtOAc in hexane) gave the title compound (0.57 g, 38%) as a colorless oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][CH3:5].[H-].[Na+].CO[C:11](=O)[CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].O>CN(C)C=O>[CH2:4]([C:3]1[N:6]=[C:11]([CH2:12][CH2:13][NH:14][C:15](=[O:16])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[O:1][N:2]=1)[CH3:5]
Reactant: CCC(=N)NO
Reactant: COC(=O)CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1noc(CCNC(=O)OC(C)(C)C)n1
Temperature: 50 °C
Reaction time: 0.1 h

Procedure:
2.00 g (22.70 mmol) N-hydroxy-propionamidine are placed in 10 ml dimethylformamide and molecular sieve. 0.999 g (24.97 mmol) sodium hydride (60% in mineral oil) are added. The mixture is stirred for 0.1 hours at 50° C., then 5.00 g (24.60 mmol) methyl3-tert-butoxycarbonylamino-propionate in 20 ml dimethylformamide are added. The reaction mixture is stirred for 3 hours at 50° C. After cooling 15 ml of water are added, and the mixture is suction filtered through Celite. The 2 phases of the filtrate are separated and the organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:19])[CH3:18].C(=O)(O)[O-].[Na+]>CCO.C1COCC1>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17](=[O:19])[CH3:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CC(=O)c1ccccc1N
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 80 °C
Reaction time: 14 h
Yield: 46.6 %

Procedure:
A mixture of 5-bromo-2,4-dichloropyrimidine (1.25 g, 5.5 mmol) and 1-(2-aminophenyl)ethanone (675 mg, 5.0 mmol) with sodium bicarbonate (1.26 g, 15.0 mmol) in 4:1 EtOH/THF (7.5 mL) was stirred at 80° C. for 14 hours. The reaction was cooled to room temperature and the resulting mixture was filtered, washing the solid with cold EtOH. The collected solid was stirred in hot water, filtered, and the resulting solid washed with cold EtOH. The solid was then dried under vacuum to give 1-{2-[(5-bromo-2-chloropyrimidin-4-yl)amino]phenyl}ethanone (761 mg, 47%) as a yellow solid. 1H NMR (DMSO-d6): δ 11.91 (s, 1H), 8.60-8.64 (m, 2H), 8.15 (d, 1 H), 7.74 (t, 1 H), 7.31 (t, 1 H), 2.72 (s, 3 H). MS m/z 326 (M+1).
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[S:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:25]([O:27]CC)=[O:26].Cl>C1(C)C=CC=CC=1>[CH3:34][O:33][C:32]1[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[S:21][CH3:1]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(OC)c(SCl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)O)cc1SC
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Triphenylphosphine (20.5 g; 78.2 mmol) was introduced a little at a time into a solution of 5c (5.1 g; 18.3 mmol) in toluene (50 ml). The reaction mixture was stirred at room temperature for 4.5 h. The precipitate (triphenylphosphine oxide) was filtered off, and the yellow filtrate was extracted with 10% strength aqueous sodium hydroxide solution (4×). Dimethyl sulfate (2 ml) was added to the combined aqueous extract, and the reaction mixture was stirred at room temperature for 2 h. The precipitate obtained was dissolved by heating to reflux temperature. The clear solution was cooled and adjusted to pH 1 using 20% strength hydrochloric acid. The precipitate (7c) was filtered off, washed with H2O and dried under reduced pressure over CaCl2.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>ClCCl.C(O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3F)ccc21
Yield: 45 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 45% of theory, C26H25FN6O3 (488.5) Rf value: 0.05 (silica gel; dichloromethane/ethanol=4:1) ##EQU58##
Reaction SMILES: [CH2:1]([C:8]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCC.Br[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=1)=[O:50]>>[CH2:21]([C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][CH:54]=2)=[O:50])[CH:13]=1)=[O:11])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Reactant: CCCCCCCC(=CC(=O)c1c[nH]c2ccccc12)CCCCCCC
Agent: CCCCCCC(=O)c1c[nH]c2ccccc12
Product: CCCCCCCC(=CC(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12)CCCCCCC

Procedure:
The procedure of Ex. 1 was repeated except that 3-(3-heptyl-2-decenoyl)indole obtained in Pre. Ex. 26 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate was used in place of 4-bromobutyrate to give 4-methoxybenzyl 4-[3-(3-heptyl-2-decenoyl)-1-indolyl]butyrate as an oil.