Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][N:7]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5]1
Reactant: OCCN1CCCNCC1
Reactant: Clc1nc2ccccc2o1
Solvent: CN(C)C=O
Product: OCCN1CCCN(c2nc3ccccc3o2)CC1
Reaction time: 17 h
Yield: 26.6 %

Procedure:
A 2.329 g portion of homopiperazine dissolved in 10 ml of THF was mixed with 830 mg of iodoethyl alcohol to carry out 24 hours of reaction at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was purified by Sephadex LH-20 (Pharmacia) (chloroform:methanol=1:1) and Diaion HP-20 (Mitsubishi Chemicals) to obtain 305 mg of 1-(2-hydroxyethyl)homo-piperazine. Next, Under cooling with ice, 150 mg of 1-(2-hydroxyethyl)homopiperazine and 159 mg of 2-chlorobenzoxazole were added to 3 ml of DMF, and the reaction was carried out for 17 hours at the same temperature and then for 24 hours at room temperature. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of ethyl acetate, washed with sodium hydrogencarbonate aqueous solution (pH 8) and water in that order, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=30:1) to obtain 72 mg of the title compound.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][OH:33])[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+:35]>O1CCOCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][OH:33])[C:27]([O-:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:35]
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C([O-])C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 11.5 g of the product of Step B in 30 ml of dioxane and 25 ml of 2N sodium hydroxide was stirred for one hour in a water bath at 50° C. and was then iced for 10 minutes and vacuum filtered. The recovered precipitate was rinsed with 50% aqueous dioxane, with a 1-1 ether-dioxane mixture and then ether and was dried to obtain 11.05 g of the syn isomer of sodium 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetate. Treatment of the salt with aqueous methanol in the presence of hydrochloric acid obtained the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetic acid.
Reaction SMILES: [Cl-].[Na+].[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[C:30]5[C:25](=[CH:26][C:27]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:28][CH:29]=5)[C:24]([CH:40]=[O:41])=[CH:23]4)=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].P([O-])([O-])(O)=[O:43].[Na+].[Na+].S.[Na]>C(O)(C)(C)C.O1CCCC1.O>[C:3]([C:7]1[N:8]=[C:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[C:30]5[C:25](=[CH:26][C:27]([O:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:28][CH:29]=5)[C:24]([C:40]([OH:43])=[O:41])=[CH:23]4)=[CH:17][C:15]=3[CH:16]=2)[S:10][CH:11]=1)([CH3:4])([CH3:6])[CH3:5]
Reactant: CCOC(=O)CCCOc1ccc2c(c1)c(C=O)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Reactant: O=P([O-])([O-])O
Agent: S
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)CCCOc1ccc2c(c1)c(C(=O)O)cn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Reaction time: 48 h
Yield: 31.3 %

Procedure:
Sodium chloride (19 mg) was added to a mixture of 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-[3-(ethoxycarbonyl)propoxy]indole-3-carbaldehyde (0.31 g), sodium hydrogenphosphate 12 water (90 mg) and 2-methyl-2-butane (0.27 ml) in a mixed solvent of water (1.5 ml), tetrahydrofuran (2.2 ml) and tert-butanol (6.5 ml). After 2 days, aqueous sodium hydrogensulfide solution was added to the mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-[3-(ethoxycarbonyl)propoxy]indole-3-carboxylic acid (0.10 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]3[CH:15]=[CH:16][S:17][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[C:11]2[CH:15]=[CH:16][S:17][C:10]=2[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=c1[nH]c(-c2ccc(Br)cc2)cc2sccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nc(-c2ccc(Br)cc2)cc2sccc12
Temperature: 100 °C

Procedure:
6-(4-Bromophenyl)-5H-thieno[3,2-c]pyridin-4-one (4.87 g) was added to phosphorus oxychloride (30 ml), and the resulting mixture was heated at 100° C. for 3 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 4-chloro-6-(4-bromophenyl)thieno[3,2-c]pyridine.
Reaction SMILES: C[C@@H]1O[C@@H]([O:8][C@H:9]2[C@H:14]([O:15]C3C4OC5=C(Cl)C=C(C=C5)[C@@H](O)[C@@H]5NC(=O)[C@@H](C6C=CC(O)=C(C7C(O)=CC(O)=CC=7[C@@H](C(O)=O)NC5=O)C=6)NC(=O)[C@H]5C(=CC=3OC3C=CC([C@@H](O)[C@@H](NC([C@H](NC)CC(C)C)=O)C(N[C@@H](CC(N)=O)C(N5)=O)=O)=CC=3Cl)C=4)[O:13][C@H:12]([CH2:95][OH:96])[C@@H:11]([OH:97])[C@@H:10]2[OH:98])C[C@@](N)(C)[C@@H]1O>Cl>[O:15]=[CH:14][C@H:9]([C@H:10]([C@@H:11]([C@@H:12]([CH2:95][OH:96])[OH:13])[OH:97])[OH:98])[OH:8]
Reactant: CN[C@H](CC(C)C)C(=O)N[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H]2C(=O)N[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)O)c4cc(O)cc(O)c4-c4cc3ccc4O)[C@H](O)c3ccc(c(Cl)c3)Oc3cc2cc(c3O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O[C@H]2C[C@](C)(N)[C@H](O)[C@H](C)O2)Oc2ccc(cc2Cl)[C@H]1O
Agent: Cl
Product: O=C[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
Total hydrolysis of AAD 216A, AAD 216A, AAD 216B and AAD 216C, individually, in 6N hydrochloric acid at reflux for 18 hours yielded no common amino acids which could be detected in a standard amino acid analysis. The presence of actinoidinic acid, which is common in the vancomycin class of antibiotics, was confirmed in the hydrolysis products by high pressure liquid chromatography and FAB mass spectrum when compared to an authentic sample. Further, hydrolysis of AAD 216A, AAD 216B and AAD 216C, individually, in IN hydrochloric acid at reflux for 4 hours yielded mannose but not ristosamine, glucosamine or vancosamine.
Reaction SMILES: [F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH2:8][CH2:7]2.[CH3:18][Mg]Br.C(OCC)C>C1COCC1.[Cu]I>[F:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9]([CH:11]([C:12]#[N:13])[C:14]#[N:15])([CH3:18])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1F)C(=C(C#N)C#N)CC2
Reactant: C[Mg]Br
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1F)C(C)(C(C#N)C#N)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of 38.2 (260 mg, 1.1 mmol) in THF (7.0 mL) was added copper(I) iodide (260 mg, 1.4 mmol) followed by a 3.0M solution of methylmagnesium bromide in diethyl ether (0.45 mL, 1.4 mmol). The mixture was heated to reflux and stirred for one hour. The reaction was then cooled to room temperature and quenched with a saturated ammonium chloride solution. The mixture was extracted with EtOAc (2×) and the combined organic layers were dried over magnesium sulfate. The residue was purified by medium pressure chromatography (silica, 25 to 50% EtOAc:hexanes) to yield 38.3 (190 mg, 68% yield). MS ESI (neg.) m/e: 243.1 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[CH3:24])=[CH:4][CH:3]=1.[C:25]([NH:30][NH2:31])(=[O:29])[CH2:26][CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:25]([NH:30][NH:31][C:21]([C:10]1[C:9]([CH3:24])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[N:11]=1)=[O:23])(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)NN
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCC(=O)NNC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.1 %

Procedure:
Added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (0.40 g, 1.05 mmol), N-butanoyl-hydrazine (0.11 g, 1.05 mmol) and EDCI (0.24 g, 1.26 mmol) dissolved in DCM (11 ml), was DMAP (0.15 g, 1.26 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 6 hrs, and then treated with 10% aq. HCl. The organic layer was collected, and evaporated under a vacuum. The crude mixture was further purified by preparative HPLC, to obtain 0.38 g (0.81 mmol, 77%) of the title compound as yellow solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:13]([CH2:27][CH3:28])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:23])[C:21]#[CH:22])=[CH:16][C:15]=1[CH:24]([CH3:26])[CH3:25])[CH3:12]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:27]([N:13]([CH2:11][CH3:12])[C:14]1[CH:19]=[CH:18][C:17]([CH:20]([OH:23])[C:21]#[C:22][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[CH:16][C:15]=1[CH:24]([CH3:26])[CH3:25])[CH3:28]
Reactant: C#CC(O)c1ccc(N(CC)CC)c(C(C)C)c1
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CCN(CC)c1ccc(C(O)C#Cc2ccc(C(=O)O)cc2)cc1C(C)C
Yield: 65.7 %

Procedure:
In a manner analogous to example 1 f, the process is carried out by a reaction of 248 mg (1 mmol) of 4-iodobenzoic acid with 350 mg (1.4 mmol) of 1-(4-diethylamino-3-isopropylphenyl)prop-2-yn-1-ol in the presence of 11 mg (0.06 mmol) of copper iodide and 20 mg (0.03 mmol) of bis(triphenylphosphine)palladium chloride. 240 mg of 4-[3-(4-diethylamino-3-isopropylphenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a whitish solid (Mp=145° C., yield=46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:9]=O)=[CH:4][CH:3]=1.[NH2:20][NH:21][C:22]([NH2:24])=[S:23].C(O)(=O)C.C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[O:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH:9]=[N:20][NH:21][C:22]([NH2:24])=[S:23])=[CH:4][CH:3]=1
Reactant: NNC(N)=S
Reactant: O=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=S)NN=CC(=Cc1ccc([N+](=O)[O-])o1)c1ccc(Br)cc1

Procedure:
1.0 g of 2-(4-bromophenyl)-3-(5-nitro-2-furyl) acrolein and 0.31 g of thiosemicarbazide are heated at reflux for 30 minutes in 25 cc of methanol with 0.3 g of glacial acetic acid and 1.0 g of sodium acetate. Upon cooling, the title compound is obtained as yellow brown crystals having a M.P. of 230°-237°.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:12][C:13]1[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=1[CH2:15][N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([NH:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: Clc1nc2c(Br)cccn2n1
Reactant: CN(Cc1ccccc1N)S(C)(=O)=O
Product: CN(Cc1ccccc1Nc1cccn2nc(Cl)nc12)S(C)(=O)=O

Procedure:
171 c) N-[2-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and N-(2-amino-benzyl)-N-methyl-methanesulfonamide (507.0 mg, 2.366 mmol) in a manner analogous to Example 2d. Product isolated as a tan foam (0.53 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.01 (d, J=6.4 Hz, 1H), 7.48-7.41 (m, 2H), 7.38 (t, J=7.4 Hz, 1H), 7.21 (t, J=7.4 Hz, 1H), 7.10 (s, 1H), 6.90-6.81 (m, 2H), 4.36 (s, 2H), 3.02 (s, 3H), 2.76 (s, 3H). MS=366 (MH)+. 171 d) N-Methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino}-benzyl)-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-benzyl]-N-methyl-methanesulfonamide (75.0 mg, 0.205 mmol) and 4-(4-methyl-piperazin-1-yl)-phenylamine (44.0 mg, 0.230 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a brown foam (0.019 g, 18%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.94 (d, J=6.5 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.45-7.39 (m, 2H), 7.35 (t, J=7.2 Hz, 1H), 7.13 (t, J=7.4 Hz, 1H), 7.00-6.94 (m, 3H), 6.81 (d, J=7.7 Hz, 1H), 6.68 (t, J=7.2 Hz, 1H), 6.60 (s, 1H), 4.36 (s, 2H), 3.18-3.13 (m, 4H), 2.91 (s, 3H), 2.78 (s, 3H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=521 (MH)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27].N1C=CC=CC=1.[Cl:35][C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:36]([Cl:35])(=[O:38])[O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCOC(=O)Cl
Temperature: 0 °C
Yield: 42.9 %

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)—N-(3-Hydroxypropyl)docosa-4,7,10,13,16,19-hexaenamide (3.0 g, 7.8 mmol) was dissolved in 40 mL of CH2Cl2 and pyridine (650 mg, 8.2 mmol) was added. Triphosgene (7.8 mmol) was then added in portions at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. until the reaction was completed, as determined by TLC. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 1.5 g of 3-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propyl carbonochloridate. (43% yield).
Reaction SMILES: CCCCCCCCCCCCCCCC(OC[C@@H](OC(CCCCCCCCCCCCCCC)=O)COC(CCC(O)=O)=O)=[O:17].ON1C(=O)CCC1=O.CN(C1C=CC=CN=1)C.[CH:65]1([N:71]=[C:72]=[N:73][CH:74]2[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]2)[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]1>C(#N)C>[C:72]([NH:71][CH:65]1[CH2:66][CH2:67][CH2:68][CH2:69][CH2:70]1)([NH:73][CH:74]1[CH2:79][CH2:78][CH2:77][CH2:76][CH2:75]1)=[O:17]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](COC(=O)CCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: O=C1CCC(=O)N1O
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 5 h

Procedure:
The targeted formulation disclosed in Example 11 of commonly owned U.S. application Ser. No. 08/851,780, filed May 6, 1997 (the disclosure of which is incorporated herein by reference), was prepared in the following manner: to a cooled (0 to 5° C.) solution of 1,2-dipalmitoyl-sn-glycero-3-succinate 66.8 mg, N-hydroxy-succinimide 11.5 mg, dimethylaminopyridine (DMAP) 2 mg and acetonitrile 40 mL in a 100 mL round bottom flask was added dropwise to a solution of dicyclohexyl carbodiimide (DCC) 20.6 mg in acetonitrile 10 mL. The resulting mixture was stirred for 5 hours. The solid material which formed during the reaction (dicyclohexylurea) was removed by filtration, and the filtrate was concentrated in vacuo to yield 78 mg of a white product of N-DPGS-succinimide.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>>[CH3:27][O:28][C:29](=[O:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][O:26][C:20]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=2[C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=2)=[CH:34][CH:33]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Reactant: COC(=O)COc1ccc(CBr)cc1
Product: COC(=O)COc1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 2-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-5-chloro-phenol (Example 48, intermediate a) and (4-bromomethyl-phenoxy)-acetic acid methyl ester (CAS Reg. No. 104508-23-8). Brown sticky solid (67%). MS (Turbo Spray): m/z=549.2 (M+H).
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:4])[NH2:2].[CH2:18]([O:25][N:26]1[C:32](=[O:33])[N:31]2[CH2:34][C@H:27]1[CH2:28][CH2:29][C@H:30]2[C:35](O)=[O:36])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:18]([O:25][N:26]1[C:32](=[O:33])[N:31]2[CH2:34][C@H:27]1[CH2:28][CH2:29][C@H:30]2[C:35]([NH:2][NH:1][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:4])=[O:36])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.2 %

Procedure:
To a solution of tert-butyl [(1R,2R)-2-(hydrazinylcarbonyl)cyclopentyl]carbamate 285 (0.15 g, 0.54 mmol) in 20 mL of DCM were added compound 1 (0.2 g, 0.82 mmol), HOBt (0.11 g, 0.82 mmol), DMAP (0.2 g, 1.64 mmol) and EDCI (0.16 g, 0.82 mmol). The mixture was stirred at room temperature for 18 h and purified by column chromatography to afford compound 286 as a solid (0.22 g, 82%).
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][C@@:8]2([CH3:35])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28](F)=[C:27]([Cl:33])[CH:26]=3)[C:9]2=[O:34])=[CH:5][CH:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[I:71][C:72]1[CH:73]=[CH:74][C:75]([C:78]2([NH2:81])[CH2:80][CH2:79]2)=[N:76][CH:77]=1>CN(C=O)C.CCOC(C)=O>[I:71][C:72]1[CH:73]=[CH:74][C:75]([C:78]2([NH:81][C:22]([C:19]3([NH:18][C:16]([C:13]4[N:12]5[C@@:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:37][CH:36]=6)([CH3:35])[C:9](=[O:34])[N:10]([C:25]6[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:33])[CH:26]=6)[C:11]5=[N:15][CH:14]=4)=[O:17])[CH2:20][CH2:21]3)=[O:24])[CH2:79][CH2:80]2)=[N:76][CH:77]=1
Reactant: NC1(c2ccc(I)cn2)CC1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ccc(I)cn5)CC4)CC3)n21
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropane-carboxylic acid (1.21 g, 2.32 mmol), HATU (970 mg, 2.55 mmol) and diisopropyl-ethylamine (808 μL, 4.64 mmol) in DMF (4 mL) was added 1-(5-iodo-pyridin-2-yl)-cyclopropylamine (724 mg, 2.78 mmol). The mixture was stirred for 1.5 h and then diluted with EtOAc (30 mL). The layers were separated and the organic layer was washed with water (3×30 mL) and brine (1×25 mL), dried with MgSO4, filtered, and concentrated to afford a crude solid. The crude material was purified by flash chromatography on silica gel, eluting with 50% hexanes in ethyl acetate (and increasing polarity to 75% ethyl acetate) to afford 1.60 g of the title compound:
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:6]([CH3:19])[CH:5]=[CH:4][N:3]=1.CO.C[O-].[Na+].[C:25](=O)(O)[O-:26].[Na+]>>[CH3:25][O:26][C:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:6]([CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: Cc1ccnc(F)c1-c1ccc2cc(N)ncc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(C)c1-c1ccc2cc(N)ncc2c1
Temperature: 50 °C

Procedure:
To a solution of 7-(2-fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine (94.8 mg; 0.374 mmol) in methanol (2.0 mL; 50 mmol) was added a solution of sodium methoxide (25 mass %) in methanol (1.0 mL; 4.5 mmol). The reaction mixture was heated at 50° C. for 5 days. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×50 mL). The combined dichloromethane extracts were dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the title compound in quantitative yield, which was carried forward without purification. LCMS (ESI): M+H=266.2; 1H NMR (400 MHz, DMSO) δ 8.80 (s, 1H), 8.04 (d, J=5.1 Hz, 1H), 7.64 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.98 (d, J=5.1 Hz, 1H), 6.65 (s, 1H), 5.92 (s, 2H), 3.76 (s, 3H), 2.10 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12])[CH:6]=O.[C:14]([O:19]CC)(=[O:18])/[CH:15]=[CH:16]/[CH3:17].CC(C)([O-])C.[K+].Cl>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][CH:16]=[CH:15][C:14]([OH:19])=[O:18])[CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12]
Reactant: COc1cc(C=O)cc(Cl)c1OC
Reactant: C/C=C/C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc(C=CC=CC(=O)O)cc(Cl)c1OC
Reaction time: 0.5 h

Procedure:
To a solution containing 10.0 g of 3,4-dimethoxy-5-chlorobenzaldehyde and 8.3 ml of ethyl crotonate in 65 ml of N-methylpyrrolidone 6.7 g of potassium tert.-butoxide was added with stirring. The solution was stirredfor 0.5 h more at 20° C. and the solution was poured then to a mixture of ice and hydrochloric acid and extracted with ether. The ether extract was washed with water and extracted then with NaHCO3 -solution. The aqueous phase was acidified with hydrochloric acid and the semisolid product was separated and washed with water. Yield 7.3 g (55%).