Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:10]([C:22]#[C:23][Si](C)(C)C)=[CH:9][C:8]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])(C)C.[OH-].[Na+].O>C1COCC1.CO>[C:6]([C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:10]([C:22]#[CH:23])=[CH:9][C:8]=1[O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])#[CH:5]
Reactant: CCCCCCCCOc1cc(C#C[Si](C)(C)C)c(OCCCCCCCC)cc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#Cc1cc(OCCCCCCCC)c(C#C)cc1OCCCCCCCC
Reaction time: 3 h

Procedure:
1,4-Bis(trimethylsilylethynyl)-2,5-di-n-octyloxybenzene (2.331 g, 4.42×10−3 mol) was dissolved in a mixture of THF (25 ml) and MeOH (25 ml). 5N NaOH (2.0 ml, 1.0×10−2 mol) was added and the solution was stirred for 3 h under Ar. Water was added to the reaction mixture. The organic layer was extracted three times with CHCl3. The combined organic layers were dried over Na2SO4. The residue was chromatographed on silica gel with 1:1 hexane:CHCl3 as the eluent. Yield=1.419 g (84% based on 2.331 g of 1,4-bis(trimethylsilylethynyi)-2,5-di-n-octyloxybenzene). 1H NMR (300 MHz, CDCl3): δ 6.95 (s, 2H, Ph-H), 3.97 (t, 8H, J=6.6 Hz, —OCH2—), 3.33 (s, 2H, —CC—H), 1.80 (quint, 4H, J=7.0 Hz, —OCH2CH2—), 1.39-1.52 (m, 4H, —OCH2CH2CH2—), 1.15-1.39 (m, 16H, —CH2—), 0.88 (t, 6H, J=6.7 Hz, —CH3). CI MS m/z: 382.285 (M+) (calcd 382.287).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][CH2:14][C:15]([OH:53])([CH3:52])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1>O.C(OCC)(=O)C>[F:13][CH2:14][C:15]([OH:53])([CH3:52])[CH2:16][O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[C:29](=[O:30])[C:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[NH:3][C:4](=[O:7])[O:5][N:45]=4)=[CH:34][CH:33]=3)=[C:27]([CH2:46][CH2:47][CH3:48])[N:26]3[N:49]=[CH:50][N:51]=[C:25]23)[CH2:20][CH2:19]1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CF)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CF)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.18 g), sodium hydrogen carbonate (0.30 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(3-fluoro-2-hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.10 g) was added, and the mixture was stirred at 90° C. for 24 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (2 mL). N,N′-Carbonyldiimidazole (0.036 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.033 mL) were added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with 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 to give the title compound as a colorless solid (0.078 g, 70%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([NH2:19])[C:7]([NH2:18])=[CH:8][C:9]=1[C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:20](=S)=[S:21].CC(O)=O>CCO.O>[Cl:3][C:4]1[C:9]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:7]2[NH:18][C:20](=[S:21])[NH:19][C:6]=2[CH:5]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(C#Cc2ccccc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: S=c1[nH]c2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1
Temperature: 110 °C

Procedure:
A 2 mL Biotage™ microwave vial was charged with solid KOH (19.4 mg, 0.345 mmol), water (0.2 mL), a solution of compound 1-2 (55.8 mg, 0.230 mmol) in EtOH (1.2 mL) and carbon disulfide (69 uL, 1.2 mmol). The vial was capped and stirred at rt until KOH dissolved, and then heated in a microwave synthesizer (Biotage Initiator™) at 110° C. for 10 min. Contents of the vial were transferred to a 20 mL scintillation vial, diluted with water (8 mL) and acidified by the dropwise addition of 10% aqueous AcOH. The resulting suspension was centrifuged, the supernatant was decanted and the resulting brownish precipitate was washed with 10% aqueous AcOH (3 mL) and water (three times 3 mL). The precipitate was dissolved in EtOAc and passed through a short plug of neutral alumina. The EtOAc solution was evaporated to dryness in vacuo to give the crude product as brownish solid. LR-MS (API-ES): calculated for C15H9ClN2S 284.0, observed m/e 285.0 (M+H)+. (Rt 2.94 min). The crude product was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][C:14]=2[F:21])[N:9]2[CH:10]=[N:11][CH:12]=[C:8]2[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].C1C[O:27][CH2:26][CH2:25]1.CC[OH:31]>>[CH2:26]([O:27][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:5]2([C:3]([OH:2])=[O:4])[N:9]3[CH:10]=[N:11][CH:12]=[C:8]3[CH2:7][CH2:6]2)=[C:14]([F:21])[CH:15]=1)=[O:31])[CH3:25]
Reactant: C1CCOC1
Reactant: CCO
Reactant: COC(=O)C1(c2ccc(C#N)cc2F)CCc2cncn21
Agent: [Li+]
Agent: [OH-]
Product: CCOC(=O)c1ccc(C2(C(=O)O)CCc3cncn32)c(F)c1

Procedure:
To a solution of 5-(4-cyano-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid methyl ester (0.250 g, 0.877 mmol) in THF/EtOH (2:1, 21 mL) is added an aqueous solution of LiOH (0.88 mL, 2 M) is added. After 2.5 h the solution is concentrated and the resulting residue is purified by HPLC (2-23% MeCN/water containing 0.1% TFA). The title compound, 5-(4-ethoxycarbonyl-2-fluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazole-5-carboxylic acid, is isolated as a minor product. MS (ESI) m/z 319.0 (M+H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][Cl:30]>C(O)C.CCOCC.O>[C:5]([CH:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][CH2:29][Cl:30])[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: ClCCCc1ccccc1CCl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccccc1CCCCl)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A stirred solution of sodium ethoxide (from 0.53 g. sodium) in ethanol (80 ml.) was treated with ethyl benzoylacetate (4.42 g.). After 1 hour, -(o-chloromethylphenyl)propyl chloride (4.57 g.) was added and stirring was continued for 24 hours. The mixture was then diluted with ether (100 ml.) and water (100 ml.). The organic layer was separated, washed with saturated brine (50 ml.), dried (MgSO4) and evaporated to give ethyl 2-benzoyl-3-(o-(3-chloropropyl)phenyl]propanoate (A) as a yellow oil (7.66 g.), NMR: 1.1 (3H,t), 2.1 (2H,m), 2.7-3.7 (6H,m), 4.1 (2H,m), 4.65 (1H,t) and 7.0-8.2 (9H,m)ppm, which was used without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1.[C:28]([Cu])#[N:29].C(Cl)Cl>CN(C=O)C>[C:28]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[N:3]=1)#[N:29]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2ccc(Oc3ccccc3C)cc2c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3C)cc2c1O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Butyl 1-bromo-4-hydroxy-6-(o-tolyloxy)isoquinoline-3-carb oxylate (130 mg, 0.30 mmol) and CuCN (54 mg, 0.61 mmol) were suspended in DMF (1.2 mL). The resulting mixture was heated to reflux for 40 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-30% EtOAc/hexanes) to give the title compound in 65 mg. MS: (−) m/z 375.29 (M−1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][CH:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C.CCOC(C)=O>CN(C=O)C>[F:17][C:13]1[CH:12]=[C:11]([CH:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:9](=[O:10])[CH2:8][S:7]2)[CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: O=C1CSC(c2cccc(F)c2)N1CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CSC(c2cccc(F)c2)N1CCCN1CCOCC1
Temperature: 60 °C
Yield: 83.2 %

Procedure:
3-(3-Chloropropyl)-2-(3-fluorophenyl)-thiazolidin-4-one (1.15 mm, 0.315 g) and morpholine (1.15 mm, 0.1 g) are mixed in 20 mL DMF in the presence of N,N-diisopropylethylamine (1.15 mm, 0.2 mL) and a catalytic amount of KI. The mixture is heated at 60° C. for 24 hours, then 20 mL of EtOAc is added to the mixture. The organic layer is washed with brine and dried. The solvent is evaporated, and the residue is triturated with hexane, 0.31 g of the product is isolated (84%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([C:17]([OH:19])=O)[CH:11]=[C:12]2[CH:16]=[CH:15][S:14][C:13]=12.[CH2:20]([N:22](CC)[CH2:23][CH3:24])[CH3:21].ClC(OCC)=O.C(NCC)C>C(Cl)(Cl)Cl>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:10]1[CH:11]=[C:12]2[CH:16]=[CH:15][S:14][C:13]2=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)=[O:19])[CH3:21]
Reactant: O=C(O)c1cc2ccsc2c(-c2ccccc2Cl)n1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCNCC
Product: CCN(CC)C(=O)c1cc2ccsc2c(-c2ccccc2Cl)n1
Yield: 40.6 %

Procedure:
Operations are carried out as for Example 7, starting from 2.9 g of 7-(2-chloro phenyl) thieno[2,3-c]pyridine 5-carboxylic acid, 1.17 g of triethylamine, 1.25 g of ethyl chloroformate and 0.94 g of diethylamine in 100 ml of chloroform. 1.4 g of N,N-diethyl 7-(2-chloro phenyl) thieno[2,3-c]pyridine 5-carboxamide, melting at 86° C., is obtained.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].C(I)C=C>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:29][CH:28]=[CH2:27])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: C=CCBr
Agent: C=CCI
Agent: [Na+]
Product: C=CCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 94.2 %

Procedure:
In the same manner as in Example 81, 984 mg of the title compound was prepared from 1.00 g of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 41, 538 mg of allyl bromide, and 415 mg of allyl iodide.
Reaction SMILES: [CH3:1][I:2].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)[NH:7][C:6](=[S:18])[NH:5]1>CC(C)=O.C(OCC)C>[IH:2].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:11][CH:12]=2)[N:7]=[C:6]([S:18][CH3:1])[NH:5]1
Reactant: CI
Reactant: CC1NC(=S)Nc2cc(C(F)(F)F)ccc21
Solvent: CC(C)=O
Solvent: CCOCC
Product: CSC1=Nc2cc(C(F)(F)F)ccc2C(C)N1
Product: I
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
Methyl iodide (0.94 ml, 15.1 mmol) was added to a suspension of 4-methyl-7-trifluoromethyl-3,4-dihydro-1H-quinazoline-2-thione (1.24 g, 5.04 mmol) in acetone (15 ml). The mixture was stirred for 3 hours (r.t.), diluted with diethyl ether and the title compound (1.66 g, 85%) was isolated from the reaction mixture by filtration as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH:10]=[CH:11][C:5]=2[CH:4]=1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)C=C2
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2

Procedure:
Here, 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane (59.2 g, 0.2 mol) is hydrogenated in glacial acetic acid (500 ml) in the presence of 10% palladium/charcoal (5 g) for 6 hours at 50° C. and at 5 bar. The catalyst is suction filtered, the glacial acetic acid is distilled off in vacuo and after the addition of water, the residue is neutralized with potassium carbonate. The precipitate is suction filtered, washed with water until free from salt and dried.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:21]=1)[O:11][CH2:12][C:13]1([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][CH2:14]1.[Li][CH2:35]CCC.[CH3:39][C:40]([CH3:42])=[O:41].[NH4+].[Cl-]>C1COCC1>[OH:41][C:40]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[CH:21]=1)[O:11][CH2:12][C:13]1([CH2:16][C:17]([O:19][CH3:35])=[O:18])[CH2:15][CH2:14]1)([CH3:42])[CH3:39]
Reactant: [Li]CCCC
Reactant: O=C(O)CC1(CO[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)CC1(CO[C@H](CCc2ccccc2C(C)(C)O)c2cccc(COC3CCCCO3)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a frozen solution of the acid of Example 14, Step 7 (2.216 g, 4.28 mmol) in 30 mL of THF at -100° C. was added 1.6M BuLi in hexanes (5.9 mL) and the mixture was stirred at -78° C. for 30 min. Acetone (630 μL, 8.6 mmol) was then added and the mixture was stirred at -78° C. for 1 hr. and was then allowed to warm to -20° C. Saturated aq. NH4Cl was then added and the products were extracted in EtOAc. At 0° C., diazomethane ~0.5M was added. When the esterification was completed, the excess of CH2N2 was quenched with AcOH. The solution was dried over Na2SO4, concentrated and stripped with toluene. Hash chromatography of the residue with EtOAc:hexane 15:85 to 35:65 afforded first, the reduced starting material (desbromo), second, the product of addition of acetone α to the ester and third, the title product.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
As in Synthetic Example 1, to 113 g of L-arginine were added 706 g of isopropyl alcohol and 302 g of water. Thereto were concurrently added dropwise 176 g of myristoyl chloride (manufactured by Nippon Oil and Fats Co., Ltd.) and 27 wt % NaOH aqueous solution over a period of 2 hours with the pH being maintained at 10.5 to 11.5 and the reaction temperature, at 10 to 13° C. After 1 hour of aging, the reaction mixture was warmed to 50° C. and adjusted to below pH 2.7 by adding concentrated hydrochloric acid to dissolve the reaction product completely. Thereafter, the pH was adjusted to 6.0 by adding 27 wt % NaOH aqueous solution to precipitate crystals and the resulting slurry was gradually cooled to 10° C. with stirring. When the slurry was cooled to 10° C., the crystals were collected by filtration and washed with 1,500 g of water and 492 g of isopropyl alcohol, successively. The resulting washed crystals were dried under reduced pressure to obtain 230 g of mono-Nα-myristoyl-L-arginine as flake-shaped crystals (yield 92.2%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:19](=[O:21])[CH3:20])[C:10]([O:14][CH2:15][CH:16]=[CH:17]C)=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[CH2:33](O)C>O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:19](=[O:21])[CH:20]=[CH:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH3:23])[CH:26]=3)[C:10]([O:14][CH2:15][C:16]([CH3:17])=[CH2:33])=[CH:11][CH:12]=2)[O:7][C:6](=[O:22])[CH:5]=1
Reactant: CCO
Reactant: CC=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: COc1cccc(C=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C)COc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-methylallyloxy-8-acetylcoumarin (2.04 g, 0.0075 mol) and 3-methoxybenzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.6 g of product m.p. 85-87° C., 1H-NMR (CDCl3) δ: 1.74 (s, 3H); 2.43 (s, 3H); 3.85-3.88 (m, 3H); 4.55 (s, 2H); 4.98 (d, 2H, J=15 Hz); 6,16 (s, 1H); 6.93 (d, 1H, J=8.9 Hz; 7.02 (d, 1H, J=16 Hz); 6.95-7.12 (m, 3H); 7.26 (m, 1H); 7.30 (d, 1H,J=16 Hz); −7.61 (d, 1H, J=8.9 Hz).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>O1CCCC1.O>[OH:6][CH:4]1[CH2:5][N:2]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CNC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
To a solution of azetidin-3-ol hydrochloride in tetrahydrofuran (90 mL) and water (10 mL) was added triethylamine (15 mL, 0.106 mol) followed by slow addition of benzyl chloroformate (8.0 mL, 0.056 mol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours then partitioned with water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash chromatography (SiO2, 25-50% ethyl acetate in hexanes) to afford phenylmethyl 3-hydroxyazetidine-1-carboxylate (3.56 g, 33% yield) as a clear and colorless oil. 1H NMR (400 MHz, CDCl3): 7.36-7.31 (m, 5H), 5.09 (s, 2H), 4.64-4.57 (m, 1H), 4.22 (dd, 2H), 3.88 (dd, 2H), 2.61 (d, 1H, J=4.0 Hz). MS (EI) for C11H13NO3: 208 (MH+).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[CH2:8](Br)[CH:9]=[CH2:10].C(=O)([O-])[O-].[Na+].[Na+].C(C(C)=O)C>CCOCC.[I-].[Na+]>[CH2:10]([CH2:1][NH:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5])[CH:9]=[CH2:8]
Reactant: CNC(C)(C)C#N
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCC(C)=O
Product: C=CCCNC(C)(C)C#N
Yield: 48.2 %

Procedure:
A mixture of 2-methylamino-2-methylpropionitrile (14.7 g., 0.15 mole) allyl bromide (18.0g., 0.15 mole), sodium carbonate (15.9 g., 0.15 mole), sodium iodide (0.2 g., 0.001 mole) and methyl ethyl ketone (200 ml.) was heated under reflux for 40 hrs. The sodium carbonate was filtered off and the solvent was removed from the filtrate in vacuo to give a yellow oil, T.L.C. (Silica, ether), three components RF 0.8, 0.4 and 0.0. The oil was passed through a column of silica 40 × 3.5 cm. using ether as an eluent to give 2-allylmethylamino-2-methylpropionitrile (10.0 g., 48%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:34]([CH3:35])[C:14]3=[N:15][CH:16]=[C:17]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH:22]4[C:30]([O:32][CH3:33])=[O:31])=[O:20])[CH:18]=[C:13]3[N:12]=2)=[CH:5][CH:4]=1)#[N:2].[ClH:36].C(=O)([O-])[O-].[NH4+:41].[NH4+].C(OCC)(=O)C.C(O)C.N>CO>[ClH:36].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:34]([CH3:35])[C:14]3=[N:15][CH:16]=[C:17]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH:22]4[C:30]([O:32][CH3:33])=[O:31])=[O:20])[CH:18]=[C:13]3[N:12]=2)=[CH:5][CH:4]=1)(=[NH:41])[NH2:2]
Reactant: [NH4+]
Reactant: COC(=O)C1Cc2ccccc2N1C(=O)c1cnc2c(c1)nc(CCc1ccc(C#N)cc1)n2C
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccccc2N1C(=O)c1cnc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C
Yield: 20 %

Procedure:
Prepared analogously to Example 1 from 2-[2-(4-cyanophenyl)ethyl]-3-methyl-6-(2-methoxycarbonyl-2,3-dihydroindol-1-yl-carbonyl)-imidazo[4,5-b]pyridine, methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 20% of theory, C27H26N6O3 (482.54) Rf value: 0.30 (silica gel; ethyl acetate/ethanol/ammonia=50:45:5) EKA mass spectrum: (M+H)+ =483
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].N1C=CC=CC=1.[CH2:30]([S:34](Cl)(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]>CN(C=O)C>[CH2:30]([S:34]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:36])=[O:35])[CH2:31][CH2:32][CH3:33]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: CCCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCS(=O)(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 342.7 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine (0.059 ml, 0.728 mmol) and 1-butanesulfonyl chloride (Aldrich) (0.063 ml, 0.485 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, extracted with EtOAc, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH/CH2Cl2), gave the title compound (0.0714 g, 34%) as a yellow solid.