Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH3:13])[C:6]=2[N:7]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>ClC1N=C(N2CCS(=O)CC2)C2N=CN=C(Cl)C=2N=1>[CH3:13][NH:12][C:8]1[C:6]2[N:7]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:3]=[C:4]([N:14]3[CH2:19][CH2:18][S:17](=[O:20])[CH2:16][CH2:15]3)[C:5]=2[N:11]=[CH:10][N:9]=1
Reactant: CNc1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Reactant: C1CNCCN1
Agent: O=S1CCN(c2nc(Cl)nc3c(Cl)ncnc23)CC1
Product: CNc1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 2-chloro-8-methylamino-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 278°-280° C.) and piperazine in dioxane at 80° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, light yellow solid (75 mg, 64%), MS (ISP) m/z=471.4 [(M+H)+], mp 168.5° C., was prepared in accordance with the general method of example 48 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and benzene-sulfonyl chloride.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([OH:23])[CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22].[OH-].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:23][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCCOCCOCCOCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCCOCCOCCOCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.16 g (128.7 mmol) of 4-fluoronitrobenzene is added to 100 g (515.0 mmol) of tetraethylene glycol, 73 g (1300 mmol) of finely powdered potassium hydroxide and 500 mg of tetrabutylammonium hydrogen sulfate in 500 ml of toluene at 0° C., and it is stirred overnight at room temperature. 1000 ml of saturated common salt solution is; added, the organic phase is separated and it is dried on magnesium sulfate. It is evaporated to dryness in a vacuum, and the residue is chromatographed in silica gel (mobile solvent: methylene chloride/isopropanol=15:1).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@@H:21](O)[CH2:22][C@@H:23]([OH:28])[CH2:24][C:25]([OH:27])=[O:26])[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:30])[CH2:9]1)=[O:6])[CH3:4].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:26][C:25](=[O:27])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:30])[CH2:9]1)=[O:6])[CH3:4]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Various portions of broth filtrate were treated at different pH-values and temperatures and of different duration, as shown in Table 1. For each set of parameters, 1,000 ml of a broth filtrate of strain AD43 (lovastatin acid concentration of 0.4 g/l) was used. After the treatment, the filtrate was brought to pH=4 using sulfuric acid, and 1,000 ml of toluene were mixed with the filtrate for 30 minutes. The layers were subsequently separated, and the toluene layer was concentrated to a volume of 80 ml by evaporation, and kept at 90° C. for 3 hours. After cooling to room temperature, the toluene was mixed with 40 ml of water, while the pH was adjusted to pH=10 with NaOH. After separation of the layers, the toluene was mixed with another 40 ml of water, while the pH was adjusted to pH=4 using sulfuric acid. After separation of the layers, 0.1 g of active coal, Norit SX Ultra, was added to the toluene solution. The toluene solution was filtered in order to remove the active coal, and subsequently concentrated to 15 ml by evaporation. Cooling to -10° C. resulted in crystallization. The crystals were filtered, washed with 5 ml of cold toluene and then dried under vacuum at room temperature. The crystals were analyzed qualitatively by TLC (Merck silicagel 60F, d=0..25 mm, art.nr. 5715; mobile phase chloroform/methanol in a ratio of 30/1), detection by UV at 254 nm (sensitivity is 0.3% at 0.1 mg of run product) and by iodine staining (sensitivity 0.1% at 0.1 mg of run product). Results of these treatments are shown in Table I.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.C(OC(Cl)=O)C(C)C.[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:28]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32](O)=[O:33])=[C:24]2[C:23](=[O:49])[N:22]([CH3:50])[C:21]1=[O:51])[CH:17]([CH3:19])[CH3:18].CN>C1COCC1.O>[CH2:16]([N:20]1[C:25]2=[N:26][N:27]([CH2:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][CH:40]=3)[C:28]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:3][CH3:1])=[O:33])=[C:24]2[C:23](=[O:49])[N:22]([CH3:50])[C:21]1=[O:51])[CH:17]([CH3:18])[CH3:19]
Reactant: CCN(CC)CC
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cccc(C(=O)O)c3)n(Cc3cccc4ccccc34)nc21
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2cccc3ccccc23)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.04 mL) followed by isobutylchloroformate (0.033 g) were added to a solution of 3-[7-isobutyl-5-methyl-2-(1-naphthylmethyl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]benzoic acid (0.08 g) in THF (1 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour. Methylamine (2M, 2 mL) was added and the mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. Reaction was diluted with water (10 mL) and extracted with dichloromethane (2×10 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified on preparative HPLC to give the title compound (0.027 g).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([CH2:8][C:9]([OH:11])=O)(C(O)=O)O>CO>[CH:9](=[O:11])/[CH:8]=[CH:3]/[CH2:2][CH2:1][CH2:1][CH2:2][CH2:3][CH3:8]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: CCCCCC/C=C/C=O

Procedure:
Twenty to 30 ml of the recovered acetal is mixed with an equal volume of 50% citric acid solution and boiled gently in a Claisen flask. Methanol is allowed to boil off until the distillate temperature reaches 95°F , at which point distillation is stopped. The flask contents are 2X water washed, followed by a 5% sodium carbonate solution. The resulting oil is vacuum distilled to yield relatively pure trans-2-nonenal. Further purification is obtained, if desired, by gas chromatography.
Reaction SMILES: [C:1]1(=[O:15])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[NH:3][C:2]1=[O:14])[N:10]=[CH:9][CH:8]=[CH:7]3.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:3]2[C:4]3[C:5](=[C:6]4[C:11](=[CH:12][CH:13]=3)[N:10]=[CH:9][CH:8]=[CH:7]4)[C:1](=[O:15])[C:2]2=[O:14])=[CH:22][CH:21]=1
Reactant: COc1ccc(CBr)cc1
Reactant: O=C1Nc2ccc3ncccc3c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)C(=O)c3c2ccc2ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a stirred solution of 1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione (Bramson, H. N. et al. J. Med. Chem. 2001, 44 (25):4339-4358) (0.15 g, 0.76 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 0.04 g, 0.98 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 1 h and 4-methoxybenzyl bromide (0.16 mL, 1.1 mmol) was added. The mixture was stirred at ambient temperature for 16 h and was diluted with water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with a 50% to 65% gradient of ethyl acetate in hexanes to afford 3-(4-methoxybenzyl)-1H-pyrrolo[3,2-f]quinoline-1,2(3H)-dione (0.20 g, 82%) as a red solid: MS (ES+) m/z 319.0 (M+1).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:14][C:15]([O:17][CH3:18])=[O:16])([CH3:13])[CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)C.[BH4-].[Na+].[Cl-].[Li+]>C(O)C.O1CCCC1>[CH3:18][O:17][C:15]([NH:14][C:5]([CH3:13])([CH2:6][CH2:7][C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][OH:3])=[O:16]
Reactant: CCOC(=O)C(C)(CCc1cccs1)NC(=O)OC
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)NC(C)(CO)CCc1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
2-Methoxycarbonylamino-2-methyl-4-(2-thienyl)butanoic acid ethylester (14.7 g, 51.6 mmol) obtained in Example 1 (c) was dissolved in a mixture of ethanol (150 ml) and tetrahydrofuran (100 ml), and then sodium borohydride (5.07 g, 0.13 mol) and lithium chloride (5.68 g, 0.13 mol) were added thereto followed by stirring overnight at room temperature under a nitrogen atmosphere. And next morning, sodium borohydride (5.07 g, 0.13 mol) and lithium chloride (5.68 g, 0.13 mol) were added thereto in a similar way, and the reaction mixture was stirred once more overnight at room temperature under a nitrogen atmosphere. Similar procedures described above were carried out for more two days. The reaction mixture was poured into ice-cold 10% hydrochloric acid (500 ml), and the resulting solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=2:1-1:5) to afford the title compound (11.7 g, 93% yield) as a white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:15][C:14]([C:28]2[CH:29]=[C:30]([C:34]([NH2:37])([CH3:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)=[N:13]1)[CH3:11].C(N(CC)CC)C>ClCCl>[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)=[CH:15][C:14]([C:28]2[CH:29]=[C:30]([C:34]([NH:37][S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:6])=[O:5])([CH3:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)=[N:13]1)[CH3:11]
Reactant: CCn1nc(-c2cccc(C(C)(C)N)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
2,2,2-trifluoroethanesulfonyl chloride (0.83 mL, 7.7 mmol, 1.5 equiv) was added to a solution of 2-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)propan-2-amine (2.0 g, 5.1 mmol, 1 equiv) and triethylamine (1.1 mL, 7.7 mmol, 1.5 equiv) in dichloromethane (51 mL) at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, and then the cooling bath was removed. After stirring for 20 minutes, the reaction mixture was partitioned between dichloromethane and citric acid solution (1 M). The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography on silica gel (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (2.04 g, 74%) as a white solid. Calcd (M+1)+: 536.1. Found: 536.1. 1H NMR (600 MHz, cdcl3) δ 7.92 (s, 1H), 7.70 (d, J=7.3, 1H), 7.65 (d, J=8.7, 2H), 7.48-7.39 (m, 2H), 7.22 (d, J=8.6, 2H), 6.06 (s, 1H), 5.01 (s, 1H), 4.11 (q, J=7.3, 2H), 3.42 (q, J=8.9, 2H), 1.83 (s, 6H), 1.45 (t, J=7.3, 3H).
Reaction SMILES: [CH3:1][N:2]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:11])[C:3]([CH3:9])([C:5]([O:7][CH3:8])=[O:6])[CH3:4].Cl>C(O)C.[Fe]>[NH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:10]([N:2]([CH3:1])[C:3]([CH3:4])([C:5]([O:7][CH3:8])=[O:6])[CH3:9])=[O:11])=[CH:13][CH:14]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)C(C)(C)N(C)C(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)C(C)(C)N(C)C(=O)c1ccc(-c2ccc(N)cc2)cc1
Yield: 81.7 %

Procedure:
As shown in Reaction Scheme 11, to a solution of methyl N,2-dimethyl-N-[(4′-nitrobiphenyl-4-yl)carbonyl]alaninate (1.92 g, 5.4 mmol) in 85% ethanol (50 mL) was added iron powder (3.01 g, 53.88 mmol) and 2 M aqueous HCl solution (2.69 mL, 5.4 mmol). The resulting mixture was heated at reflux for 2.5 h. The mixture was filtered through a pad of Celite® and concentrated under reduced pressure to afford methyl N-[(4′-aminobiphenyl-4-yl)carbonyl]-N,2-dimethylalaninate as a yellow solid (1.44 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 1.42 (s, 6H), 2.94 (s, 3H), 3.57 (s, 3H), 5.30 (broad s, 2H), 6.61 (d, 2H), 7.31-7.40 (m, 4H), 7.58 (d, 2H); LC-MS m/z 327.2 (MH+), retention time 1.84 minutes.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[Cl:32])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[C:36]([O:35][C:33]([N:7]1[CH2:8][CH2:9][C@H:10]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([C:24]4[C:29]([F:30])=[CH:28][CH:27]=[C:26]([F:31])[C:25]=4[Cl:32])[CH:20]=3)=[CH:15][CH:16]=2)[C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccc(OCc2cc(-c3c(F)ccc(F)c3Cl)no2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(OCc3cc(-c4c(F)ccc(F)c4Cl)no3)cc2)[C@@H](C(=O)O)C1
Yield: 99.9 %

Procedure:
A sol. of compound D1 (2.00 g, 3.72 mmol) in THF (30 mL) and aq. 1M NaOH (30 mL) was stirred at 70° C. overnight. Aq. 1M HCl was added until a pH=4 was reached. The mixture was extracted with EtOAc (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Drying under high vacuum yielded the crude title compound (2.04 g, quantitative yield) that was used further without purification. LC-MS: tR=1.08 min; ES+: 549.31.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:12][C:13]([NH:15][C:16]1([C:19]([OH:21])=O)[CH2:18][CH2:17]1)=[O:14])[CH2:9][CH2:10][CH3:11].[NH2:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].O>O1CCOCC1.C(OCC)(=O)C>[CH2:8]([O:12][C:13]([NH:15][C:16]1([C:19]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])=[O:29])[CH2:24][CH:25]([CH3:26])[CH3:27])=[O:21])[CH2:17][CH2:18]1)=[O:14])[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)C[C@H](N)C(=O)NCC(N)=O
Reactant: CCCCOC(=O)NC1(C(=O)O)CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CCCCOC(=O)NC1(C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)CC1
Reaction time: 20 h

Procedure:
1.7 ml of triethylamine and 3.6 g of the N-hydroxysuccinimide ester of 1-butoxycarbonylaminocyclopropane-1-carboxylic acid were added to 2.3 g of L-leucyl-glycinamide in 30 ml of dioxane at 10° C., the reaction mixture was stirred for 1 hour at this temperature, 10 ml of water were added and the reaction was continued for 20 hours at room temperature. In the working up procedure, the mixture was taken up in ethyl acetate and the solution was washed successively with 10% strength aqueous citric acid solution, sodium carbonate solution and water, dried over sodium sulfate and evaporated down under reduced pressure. The residue was purified by chromatography over a silica gel column (elution with 10:1 dichloromethane/methanol) to give 3.1 g of 1-butoxycarbonylaminocycloprop-1-yl-carbonyl-L-leucyl-glycinamide.
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][N:7]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:6]1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[CH2:18]([O:17][C:15]([N:7]1[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8]1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CC12CCCCC2
Temperature: 35 °C
Reaction time: 6 h
Yield: 88.9 %

Procedure:
To a solution of (6) (300 mg; 0.9 mmol) in a mixture dioxane/water (6 mL; 9:1) was added a 2 M solution of NaOH (0.90 mL; 1.8 mmol). The reaction mixture was stirred at 35° C. for 6 hours. Solvents were removed in vacuo. The residue was diluted in water (15 mL) and was washed with diethyl ether (3×10 mL). The aqueous phase was acidified with 2N HCl and was extracted with ethyl acetate (3×15 mL). The ethyl acetate extracts were combined, dried over MgSO4, and concentrated to give 254 mg (0.8 mmol, 89%) of (7) as a colorless gum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.OC1C=CC(C2CC(C3C=CC(O)=CC=3)CCC=2)=CC=1.CC(C1C=CC=CC=1)=C>[C].[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2=CC(c3ccc(O)cc3)CCC2)cc1
Agent: [Pd]
Agent: C=C(C)c1ccccc1
Agent: Oc1ccc(C2=CCCC(c3ccc(O)cc3)C2)cc1
Product: Oc1ccc(-c2cccc(-c3ccc(O)cc3)c2)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 53 %

Procedure:
After the water layer was separated, the oil layer was condensed or otherwise adjusted so that the concentration of the mixture of 1,3-bis(4-hydroxyphenyl)-1-cyclohexene and 1,5-bis(4-hydroxyphenyl)-1-cyclohexene became 17%. 79.6 g of the concentration-adjusted solution, 14.8 g of α-methyl styrene and 0.8 g of 5% palladium carbon were introduced to an autoclave and agitated for 6 hours at 150° C. After the reaction, the reaction liquid was filtered to remove the 5% palladium carbon, and then the methyl isobutyl ketone was distilled out, after which 40 g of toluene was added and the separated crystal was filtered out and dried to obtain 6.9 g of 4,4″-dihydroxy-m-terphenyl of 97% purity (high-speed liquid chromatography) [Step (C)].
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.[CH3:10][Mg]Br>C1COCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C:6]([CH3:10])([OH:9])[CH2:5][CH2:4]1
Reactant: C[Mg]Br
Reactant: O=C1CCC(CO)CC1
Solvent: C1CCOC1
Product: CC1(O)CCC(CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-(hydroxymethyl)cyclohexanone (1.0 g, 7.8 mmol) in THF (20 mL) was added methyl magnesium bromide (3.0 M in Et2O, 7.8 mL, 23.4 mmol) dropwise at 0° C. for 5 min. The mixture was allowed to warm to room temperature and stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 80% EtOAc/hexane as eluent) to provide compound A112-1 (300 mg, 27%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23]Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH2:21][CH2:22][CH2:23][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:20])=[O:19])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCCl)cc3)nc12
Reactant: C1CCNCC1
Product: Cc1cccn2cc(-c3ccc(NS(=O)(=O)CCCN4CCCCC4)cc3)nc12
Temperature: 25 °C

Procedure:
The product of Step A (65 mg) and piperidine (1.0 mL) were heated at 100° C. for 1.5 hours. The reaction was cooled to ambient temperature and partitioned between ethyl acetate (15 mL) and saturated sodium bicarbonate solution (15 mL). The aqueous portion was extracted with a fresh portion of ethyl acetate (15 mL) (2×) and the organic portions combined and washed with brine (15 mL). The organic portions were dried over magnesium sulfate, filtered and evaporated. The residue was purified via silica gel chromatography (dichloromethane/methanol) to give the title compound (26 mg).). 1H-NMR (CD3OD) δ 1H-NMR (CD3OD) δ8.14 (d, J=7.0 Hz, 1H), 8.00 (s, 1H), 7.81 (m, 2H), 7.23 (m, 2H), 6.98 (m, 1H), 6.70 (t, J=7.0 Hz, 1H), 3.07 (m, 2H), 2.49 (s, 3H), 2.31 (m, 6H), 1.87 (m, 2H), 1.44 (m, 4H), 1.33 (m, 2H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:28][C@H:29]([C:31]([OH:33])=[O:32])[CH3:30]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:28][C@@H:29]([CH3:30])[C:31]([OH:33])=[O:32])=[O:7]
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(OC)cc3)ccc2c1O
Product: COc1ccc(Oc2ccc3c(O)c(C(=O)N[C@@H](C)C(=O)O)ncc3c2)cc1

Procedure:
Prepared in analogy to Example A-63 g) from 7-(4-methoxy-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (of Example of A-66 a) and L-alanine. MS-(−)-ion: M-1=381.13.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:15])([CH:13]=[CH2:14])[C:5]([OH:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:17][CH:18]=[CH2:19]>CN(C=O)C.CCOCC>[CH2:19]([O:12][C:5]([CH3:11])([C:4]([F:15])([F:3])[CH:13]=[CH2:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:18]=[CH2:17]
Reactant: C=CC(F)(F)C(C)(O)C(=O)OCC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCOC(C)(C(=O)OCC)C(F)(F)C=C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% NaH (48.5 mg, 1.212 mmol) was added to a cold (−20° C.) solution of ethyl 3,3-difluoro-2-hydroxy-2-methylpent-4-enoate (214 mg, 1.102 mmol) in DMF (2 mL) and the mixture was allowed to warm to rt (˜30 min) and then 3-bromoprop-1-ene (0.113 mL, 1.323 mmol) was added. The mixture was stirred at rt overnight, diluted with ether (20 mL) and washed with water, brine and dried (MgSO4). The crude product was purified by silica gel FCC (2:1 DCM-hexanes) to afford ethyl 2-(allyloxy)-3,3-difluoro-2-methylpent-4-enoate as a clear oil.