Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[C:32]([C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:32]([C:36]1[CH:37]=[CH:38][C:39]([CH2:40][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2/[CH:22]=[CH:21]/[CH:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:42][CH:43]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)Cc2ccc(C#N)cc2)cc1
Yield: 98 %

Procedure:
A solution of 1.4 g (3.13 mmol, 92% pure) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate (Example 75A) in 7 ml of dry acetonitrile is mixed with 1.42 g (6.26 mmol) 4-(tert-butyl)benzyl bromide and 1.30 g (9.39 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The residue is directly purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 1:5). 1.85 g (3.32 mmol, 93% purity, 98% yield) of an oil are isolated.
Reaction SMILES: N1C=CC=CC=1.[I:7]Cl.[CH3:9][CH2:10][C@@:11]1([OH:38])[C:16](=[O:17])[O:15][CH2:14][C:13]2[C:18]([N:20]3[C:24](=[CH:25][C:12]1=2)[C:23]1[N:26]=[C:27]2[C:32](=[CH:33][C:22]=1[CH2:21]3)[C:31]([CH2:34][CH:35]=[CH2:36])=[C:30]([OH:37])[CH:29]=[CH:28]2)=[O:19]>C(Cl)(Cl)Cl.[N+]([O-])([O-])=O.[Ag+]>[CH2:10]([C@:11]1([OH:38])[C:12]2[CH:25]=[C:24]3[N:20]([CH2:21][C:22]4[C:23]3=[N:26][C:27]3[C:32]([CH:33]=4)=[C:31]4[CH2:34][CH:35]([CH2:36][I:7])[O:37][C:30]4=[CH:29][CH:28]=3)[C:18](=[O:19])[C:13]=2[CH2:14][O:15][C:16]1=[O:17])[CH3:9]
Reactant: C=CCc1c(O)ccc2nc3c(cc12)Cn1c-3cc2c(c1=O)COC(=O)[C@]2(O)CC
Reactant: ClI
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3c4c(ccc3nc2-1)OC(CI)C4
Reaction time: 0.25 h

Procedure:
Silver nitrate (6.8 g, 0.040 mol) in dry, freshly distilled chloroform (50 mL) and dry pyridine (20 mL) was treated, dropwise, with stirring with a solution of iodine monochloride (6.48 g, 0.0400 mol) in dry chloroform (40 mL) over a two min period. After stirring for 15 min, the mixture was centrifuged; the supernatent was then added to a solution of (S)-9-allyl-10-hydroxycamptothecin (3.92 g, 0.00960 mol) in dry chloroform (15 mL) giving a deep amber solution which was stirred overnight at ambient temperature. The solution was concentrated to a small volume and then partitioned between methylene chloride and water. After separation of the layers, the aqueous phase was re-extracted with methylene chloride. The combined organic layer was washed successsively with ice cold 5% aq. HCl, dilute sodium thiosulfate solution, and finally with water. The solution was dried (sodium sulfate) and evaporated to a golden-brown residue which was triturated with a small amount of cold methanol to afford the title compound as a light brown solid. (2.25 g, 44%). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=4.3 Hz, 1H), 8.07 (d, J=9.2 Hz, 1H), 7.61 (s, 1H), 7.40 (dd, J=7.1 Hz and J=2.0 Hz, 1H), 5.73 (d, J=16.3 Hz, 1H), 5.29 (d, J=16.3 Hz, 1H), 5.26 (s, 2H), 5.20-5.10 (m, 1H), 3.83-3.81 (m, 1H), 3.72-3.70 (m, 1H), 3.57-3.54 (m, 1H), 3.49-3.46 (m, 1H), 3.39-3.38 (m, 1H), 1.92-1.84 (m, 2H), 1.03 (t, J=7.3 Hz, 3H). Anal.: (C23H19IN2O5.1/2H2O) calcd.: C, 51.22; H, 3.74; N, 5.19 found: C, 51.03; H, 3.56; N, 4.87.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]([CH:30]3[CH2:32][CH2:31]3)[C:16]([CH2:18][C:19]([NH:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:20])=[N:17][C:13]=2[C:12]([F:33])=[C:11]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)[C:10]=1[F:41])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)[CH:44]=[O:45]>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]([CH:30]3[CH2:32][CH2:31]3)[C:16]3=[CH:18][C:19](=[O:20])[N:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:44](=[O:45])[N:17]3[C:13]=2[C:12]([F:33])=[C:11]([N:34]2[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]2)[C:10]=1[F:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(nc(CC(=O)NOCc4ccccc4)n3C3CC3)c2F)CC1
Reactant: CN(C)C=O
Product: CN1CCN(c2c(F)c(NCc3ccccc3)c3c(c2F)n2c(=O)n(OCc4ccccc4)c(=O)cc2n3C2CC2)CC1
Yield: 21 %

Procedure:
2-[7-Benzylamino-1-cyclopropyl-4,6-difluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-N-benzyloxy-acetamide (2.6 g, 4.64 mmol) is reacted with N,N'-carbonyldiimidazole (1.5 g, 9.28 mmol) in dimethylformamide (50 ml) at room temperature for 1 day. At the end of the reaction, the volatiles are evaporated under reduced pressure and the residue chromatographed on silica gel (eluent: 5% methanol-dichloromethane). The relevant fractions are concentrated in vacuo until crystals form. Filtration affords 0.57 g of 6-benzylamino-2-benzyloxy-5-cyclopropyl-7,9-difluoro-8-(4-methyl-piperazin-1-yl)-1,2,3,5-tetrahydro-pyrimido[1,6-a]benzimidazole-1,3-dione as colorless crystals (21%): mp: 214° C.; NMR (DMSO-d6): 0.97 (m,2H),1.18(m,2H),2.23(s,3H),2.42(m,4H),3.13 (m,5H),4.35(d,J=6.5 Hz,2H),5.05(s,2H),5.36(s,1H),7.22-7.61 (m,11H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[C:13]([O-])(O)=[O:14].[Na+]>CO>[OH:14][CH2:13][CH2:4][CH2:3][CH2:2][C:1]([O:6][CH3:5])=[O:7]
Reactant: O=C([O-])O
Reactant: O=C1CCCCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCO
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
To prepare 2, freshly distilled δ-valerolactone (1) (856 mg) in methanol (17 ml) was treated with concentrated H2SO4 (100 μl) and refluxed for 12 hours. The solution was cooled to −20° C., treated with NaHCO3 (80 mg), and stirred for 10 minutes. The reaction mixture was filtered and the solvent was removed in vacuum. The residue was taken up in DCM (10 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give methyl 5-hydroxypentanoate (2) (Huckstep et al., Synthesis 10:881-82 (1982), which is hereby incorporated by reference in its entirety) (1071 mg, 94%) as a colorless oil, which was used directly without any further purification. 1H NMR (400 MHz, acetone-d6): δ 1.55 (2H, m), 1.68 (2H, m), 2.35 (2H, t, J=7.4 Hz), 3.57 (2H, m), 3.64 (3H, s); 13C NMR (100 MHz, acetone-d6): δ 22.2, 32.9, 34.1, 51.5, 61.9, 174.2. See FIGS. 75A-B.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([O:14][CH3:15])=[O:13])[CH2:10]I)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:10][CH:23]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)[C:24](=[O:26])[CH3:25])[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(CC(C(C)=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-3-iodo-L-alaninate (215 g, 652 mmol) and 4-chlorophenylacetone (100 g, 593 mmol) in dry N,N-dimethylformamide (1.5 L) was added cesium carbonate (483 g, 1483 mmol) at room temperature. After 4 h, the mixture was then added to a stirring solution of pH 7 buffer and EtOAc. The aqeuous layer was extracted with EtOAc and the combined organics were washed with pH 7 buffer, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (10% ethyl acetate/heptane→30% ethyl acetate/heptane) to provide the title compound as a mixture of diastereomers (150 g). MS 392.1 (M+Na).
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[OH:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C=O.[CH:27](O)=[O:28]>>[OH:28][CH2:27][C:11]1[C:12]2[C:4]3[CH2:3][N:2]([CH3:1])[CH2:24][CH2:23][C:5]=3[N:6]([CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[OH:16])[C:7]=2[CH:8]=[CH:9][C:10]=1[CH3:13]
Reactant: O=CO
Reactant: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Agent: C=O
Product: Cc1ccc2c(c1CO)c1c(n2CC(O)c2ccncc2)CCN(C)C1
Yield: 7.1 %

Procedure:
2-(2,8-Dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol (350 mg, 1 mmol), formaldehyde (37%, 0.89 g, 10 mmol) and formic acid (922 mg, 20 mmol) was stirred at 100° C. for 12 h. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was washed with saturated sodium bicarbonate and extracted with DCM (2×25 mL). The combined organic layer was washed with water (5×25 mL) dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was subjected to preparative HPLC to obtain 25 mg of 2-(9-(hydroxymethyl)-2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(pyridin-4-yl)ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.56 (d, 2H), 7.29 (d, 2H), 7.12 (d, 1H), 6.98 (d, 1H), 4.9 (dd, 1H), 4.79 (q, 2H), 4.13 (m, 2H), 3.78 (d, 1H), 3.72 (d, 1H), 3.0 (m, 1H), 2.8 (m, 1H), 2.67 (m, 2H), 2.49 (s, 3H), 2.32 (s, 3H). Separation by chiral HPLC provided diastereomers II-150a-d.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].O[Li].O.Cl>CO.O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:30][CH3:31])=[C:10]([CH2:19][NH:20][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)OC
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To methyl 5-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-5-oxopentanoate (0.450 g, 1.043 mmol) in MeOH/H2O was added LiOH.H2O and stirred at room temperature for 16 h. The mixture was the acidified with HCl (1 N) and extracted with DCM/i-PrOH (3/1) which was dried over Na2SO4 and concentrated to afford the title compound (0.3606 g, 82.84%). LC-MS m/z 418 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1.[CH:22]1(C=O)C[CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH:18]4[CH2:23][CH2:22]4)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:19])[CH:4]=1
Reactant: CCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21
Reactant: O=CC1CC1
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)CCCN3CC1CC1

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1=H, n=1) and cyclopropanecarboxaldehyde. 1H NMR (400 MHz, CDCl3) 11.44 (br. s, 1H), 7.06 (s, 1H), 7.00 (s, 1H), 6.92 (s, 1H), 3.40 (t, 2H, J=5.6), 3.21 (d, 2H, J=6.2), 2.90 (t, 2H, J=6.3), 1.99 (m, 2H), 1.07 (m, 1H), 0.58 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10][CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[N:9][C:5]=2[CH:4]=1.[OH2:21]>>[OH:1][CH2:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8]([S:10]([CH2:11][C:12]3[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][CH:13]=3)=[O:21])=[N:9][C:5]=2[CH:4]=1
Reactant: O
Reactant: Nc1cccc(CSc2nc3cc(CO)ccc3[nH]2)n1
Product: Nc1cccc(CS(=O)c2nc3cc(CO)ccc3[nH]2)n1

Procedure:
The title compound was prepared by the method of Example 85 using 350 mg of 6-[[[5-(hydroxymethyl)-1H-benzimidazol-2-yl]thio]methyl]-2-pyridinamine (see Example 104) instead of 6-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Analysis. Calc'd. for C14H14N4SO2*¼ H2O: C, 54.80; H,4.60; N, 18.25; S, 10.44. Found: C, 54.85; H, 4.70; N, 18.01; S, 10.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].C(N(CC)CC)C.Cl[C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>ClCCl>[CH3:13][O:12][C:8]1[CH:7]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])[NH:6][C:22](=[O:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1cc(OC)c(OC)c(OC)c1
Reaction time: 2 h

Procedure:
3,4,5-Trimethoxyaniline (3.0 g) and triethylamine (4.5 mL) were dissolved in dichloromethane (10 mL), ethyl chloroglyoxylate (1.89 mL) was added dropwise to the solution under ice cooling, and the mixture was stirred for 2 hours. 1 M Hydrochloric acid was added to the reaction mixture to conduct extraction with dichloromethane. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][CH2:11][C:12]([OH:14])=[O:13].[OH-].[Na+]>Cl>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cc(O)cc(=O)o1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(O)cc(=O)n1CC(=O)O

Procedure:
178.7 g (1.4 mmol) of 4-hydroxy-6-methyl-2H-pyran-2-one are added, in portions at room temperature, to a solution of 106.4 g (1.4 mmol) of glycine in 1.4 l of a 1 N aqueous sodium hydroxide solution. The mixture is heated under reflux for 1 hour, the reaction medium is cooled and it is acidified with 500 ml of 3 N hydrochloric acid. The reaction medium is then concentrated to half the volume, the precipitate is filtered, it is washed with cold water and it is dried in an oven.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[N:10][CH:9]=1
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1-c1ccnnc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CC(=O)O)ccc1-c1ccnnc1

Procedure:
The ester 134-2 obtained in step 2 was stirred in DCM (15 ml) with trifluoroacetic acid (TFA, 3 ml) at room temperature overnight. After concentrated by evaporation, the residue was redistributed between ethyl acetate (30 ml) and 5% Na2CO3 aqueous solution (30 ml). The aqueous phase was acidified to pH around 2 with 6 N HCl solution and extracted with ethyl acetate (40 ml×2). The organic extraction was evaporated to give 2-(3-methyl-4-(pyridazin-4-yl)phenyl)acetic acid 134-3 as a solid which is used for reaction without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[OH:19][C@@H:20]([CH2:33][NH2:34])[CH2:21][O:22][C:23]1[C:31]2[NH:30][C:29](=[O:32])[NH:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.C(O)(=O)C>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:34][CH2:33][C@H:20]([OH:19])[CH2:21][O:22][C:23]3[C:31]4[NH:30][C:29](=[O:32])[NH:28][C:27]=4[CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1
Yield: 48.4 %

Procedure:
A mixture of 1-(4-ethoxycarbonylphenyl)-4-piperidone (0.25 g, 1 mmol) (Taylor, E. C., Skotnicki, J. S. Synthesis, 1981, 606) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (0.22g, 1 mmol) (U.S. Pat. No. 5,786,356/1998) in 100 mL of ethanol and 0.5 mL of acetic acid was hydrogenated in the presence of 400 mg of 10% palladium on carbon under hydrogen (5˜20 psi) for overnight. The catalyst was then removed by filtering through a short pad of silica gel. The filtrate was concentrated and purified by thin layer chromatography (12% methanol/methylene chloride) to give the title compound as a white solid (0.22 g, 48%); mp >170° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.28 (t, J=7.0 Hz, 3H), 1.30-1.55 (m, 2H), 1.80-2.10 (m, 2H), 2.80-3.10 (m, 5H), 3.80-4.10 (m, 5H), 4.23 (q, J=7.0 Hz, 2H), 6.58 (d, J=7.8 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 6.86 (dd, J=8.4, 7.8 Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 10.60 (s, 1H), 10.75 (s, 1H); MS (ES) m/z: 455.1 (MH+); HRMS Calcd. for C24H30N4O5 (MH+): 454.2216. Found: 454.2211.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:32]4[CH:31]=[C:30]([Br:29])[CH:34]=[N:33]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Reactant: Brc1cn[nH]c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(Br)cn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 6, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-Bromo-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[CH3:23][N:24]([C:4](=[O:6])[CH:3]=[C:2]([CH3:1])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])[CH2:25][CH2:26][OH:27]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: CNCCO
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)N(C)CCO
Yield: 92 %

Procedure:
The procedure of Example 1 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 2.4 ml of N-methylethanolamine were used. 6.6 g (yield 92%) of the title compound was obtained as a colorless oil.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[C:10](#[N:12])[CH3:11]>>[CH:6]1([C:4](=[O:5])[CH2:11][C:10]#[N:12])[CH2:7][CH2:8][CH2:9]1
Reactant: CCOC(=O)C1CCC1
Reactant: CC#N
Product: N#CCC(=O)C1CCC1

Procedure:
The title compound was prepared in analogy to example 101 step A from cyclobutanecarboxylic acid ethyl ester and acetonitrile. Light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.[CH3:13]O>>[CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([O:8][CH3:13])=[O:7]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: Cl
Product: COC(=O)c1ccc(C)cc1O
Temperature: 60 °C
Yield: 94 %

Procedure:
To a suspension of 10 g (0.0651 mol) of 4-methylsalicylic acid in 150 mL of methanol was added 50 mL of ethereal hydrochloric acid. The reaction mixture was heated at 60° C. for 60 hours. The solvent was removed under vacuum. After adding hexane-ethyl acetate, the resulting solid was filtered and the filtrate was evaporated to give 10.2 g (94%) of product as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][NH:25][CH:26]2[CH3:29])=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][C:19]([C:15]5[O:14][CH:18]=[CH:17][CH:16]=5)=[CH:20][CH:21]=4)[CH:26]3[CH3:29])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2ccc(-c3ccco3)cc21
Product: CC1c2cc(-c3ccco3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-Furan-2-yl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:13]([OH:23])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][C@@H:12]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:13]([OH:23])[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OCC(O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(O)[C@@H](N)Cc1ccccc1

Procedure:
5% Palladium-carbon (130 mg) is added to a solution of (2RS,3S)-3-(benzyloxycarbonyl)amino-1-(tert-butyldimethylsilyl)oxy-4-phenyl-2-butanol (130 mg, Reference compound No. 15-1) in methanol (5 ml), and the mixture is stirred under a hydrogen atmosphere (1 atm) for three hours. The reaction mixture is filtered to remove the catalyst. The filtrate is concentrated under reduced pressure to give the titled reference compound (89.2 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][S:14]([CH2:17][C:18](NC1N=NN(CCCCCCCCCCCC)N=1)=[O:19])(=[O:16])=[O:15])([CH3:3])[CH3:2].[CH2:38]([SH:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:38]([S:44][C:18](=[O:19])[CH2:17][S:14](=[O:15])(=[O:16])[NH:13][C:5]1[C:6]([CH:10]([CH3:12])[CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCS
Reactant: CCCCCCCCCCCCn1nnc(NC(=O)CS(=O)(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Product: CCCCCCSC(=O)CS(=O)(=O)Nc1c(C(C)C)cccc1C(C)C

Procedure:
This compound was prepared in the same manner as for the title compound of Example 2, except that 2-DAT was replaced with hexanthiol, mp 81°-83° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)[O:16][C:15](=O)[C:12]2([CH2:14][CH2:13]2)[C:11](=[O:18])[O:10]1>C(O)C>[O:16]=[C:15]1[CH:12]([C:11]([OH:18])=[O:10])[CH2:13][CH2:14][N:1]1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2ccccc2)C1=O
Yield: 75.6 %

Procedure:
A mixture of aniline (0.803 mL; 8.82 mmol) and 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.5 g; 2.94 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 30 to 100% ethyl acetate in heptane with 5% acetic acid) to afford 0.456 g (76%) of 2-oxo-1-phenylpyrrolidine-3-carboxylic acid.