Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](/C=C/CCO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of the TBDPS-protected alcohol 8b (584 mg, 1.10 mmol, crude) in dry THF (9 mL) at 0° C. was added TBAF (1.0M/THF, 1.38 mL, 1.38 mmol), and the reaction mixture was allowed to warm to rt while stirring under argon for 3.5 h, then quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 194 mg (60%, 2 steps) of the title compound as a colorless oil. [α]D23−6.4 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 7.20-7.40 (m, 5H), 5.65-5.49 (m, 1H), 5.44 (dd, 1H, J=15.3, 6.6 Hz), 5.09 (s, 2H), 4.67 (bs, 1H), 4.16 (m, 1H), 3.63 (bs, 2H), 2.28 (q, 2H, J=6.0 Hz), 1.82 (bs, 1H), 1.65 (m, 1H), 1.40-1.25 (m, 2H), 0.80-1.00 (m, 6H); HRMS (ESI) m/z calcd for C17H25NO3Na 314.1732; found 314.1739.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:8]1[CH:9]=[C:4]([CH:3]=[N:2][OH:1])[C:5](=[O:11])[NH:6][C:7]1=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]cc(C=NO)c(=O)[nH]1
Reactant: BrCc1ccccc1
Product: O=c1[nH]c(=O)n(Cc2ccccc2)cc1C=NO

Procedure:
substituting 5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione and benzyl bromide gave 1-benzyl-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione, m.p. 172°-174° C.; and
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:29][C:30]([CH3:36])=[C:31]([C:33]([OH:35])=O)[N:32]=1)([CH3:27])[CH3:26].[O:37]1[C:42]2([CH2:47][CH2:46][N:45]([CH2:48][C:49]3[C:50]([F:58])=[C:51]([CH2:55][CH2:56][OH:57])[CH:52]=[CH:53][CH:54]=3)[CH2:44][CH2:43]2)[CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[F:58][C:50]1[C:51]([CH2:55][CH2:56][OH:57])=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][N:45]1[CH2:46][CH2:47][C:42]2([O:37][CH2:38][CH2:39][N:40]([C:33]([C:31]3[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][C:30]=3[CH3:36])=[O:35])[CH2:41]2)[CH2:43][CH2:44]1
Reactant: Cc1sc(C(C)C)nc1C(=O)O
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1sc(C(C)C)nc1C(=O)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.175 g) was added in one portion to a stirred solution at 0° C. of 2-isopropyl-5-methylthiazole-4-carboxylic acid (example 69, step b) (0.066 mg) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.109 g) and triethylamine (0.148 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.155 mg.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](Cl)=[O:48])=[CH:42][CH:41]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:32]([O:39][C:40]1[CH:41]=[CH:42][C:43]([CH2:46][C:47]([NH:21][C:18]2[C:17]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:48])=[CH:44][CH:45]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccc4ccccc4c3)n2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccc3ccccc3c2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 58.2 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(naphthalen-2-yl)pyrazin-2-amine (7e) (500 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C., and the mixture was heated with stirring at 50° C. for 16 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11e (460 mg, 681 μmol, 58.2%) as a yellow foamy solid. Rf=0.26 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.12 (s, 6H), 0.21 (s, 6H), 0.91 (s, 9H), 0.94 (s, 9H), 3.46 (s, 2H), 6.55-6.65 (AA′BB′, 2H), 6.91-6.97 (AA′BB′, 2H), 6.97-7.03 (AA′BB′, 2H), 7.47-7.58 (m, 2H), 7.75-8.00 (m, 4H), 8.08-8.14 (AA′BB′, 2H), 8.23 (s, 1H), 9.00 (s, 1H), 10.63 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.8, 17.9, 25.5 (6C), 119.4 (2C), 120.3 (2C), 125.5, 126.1, 126.6, 127.1, 127.2, 127.3, 127.5, 127.9, 128.2 (2C), 128.5, 130.2 (2C), 132.6, 132.8, 135.3, 137.6, 143.0, 147.5, 148.0, 153.7, 156.7, 169.4 (one carbon at the benzyl position was unobservable due to overlapping with the septet peak of DMSO); IR (KBr, cm−1) 478, 527, 687, 718, 746, 781, 804, 839, 914, 1009, 1082, 1103, 1128, 1169, 1261, 1362, 1415, 1445, 1472, 1508, 1605, 1670, 2857, 2886, 2928, 2955, 3057, 3221; HRMS (ESI+) m/z 698.3194 ([M+Na]+, C40H49N3NaO3Si2+ requires 698.3205).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C@H:13]1[CH2:18][CH2:17][C@H:16](O)[CH2:15][CH2:14]1.F[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl.C1C[O:34]CC1>>[CH3:11][O:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([O:34][C:21]2[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:14]1
Reactant: CO[C@H]1CC[C@H](O)CC1
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1cccnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: CO[C@@H]1CCC[C@H](Oc2ncccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
LiHMDS (1 M solution in THF; 40.0 ml) was added slowly to an ice/ethanol-cooled solution of cis/trans-4-methoxy-cyclohexanol (5.00 g) in THF (10 ml). Cooling was suspended after the addition was complete and the mixture was stirred for 15 minutes at room temperature. A solution of 2-fluoro-3-nitro-pyridine (5.10 g) in THF (10 ml) was added slowly while the temperature was maintained below 24° C. The reaction mixture was stirred for 2 h at room temperature, neutralized by addition of hydrochloric acid (1M), and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was submitted to column chromatography (silica gel, petrol ether/ethyl acetate 70:30 50:50) to give the cis-isomer (5.82 g) and the trans-isomer (1.60 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[F:10][C:11]1[CH:22]=[CH:21][C:14]2[NH:15]C(=O)[O:17][C:18](=O)[C:13]=2[CH:12]=1.C[Al](C)C.Cl>C1(C)C=CC=CC=1>[NH2:15][C:14]1[CH:21]=[CH:22][C:11]([F:10])=[CH:12][C:13]=1[C:18]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Br:1])[C:3]=1[CH3:9])=[O:17]
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: Cc1c(N)cccc1Br
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1c(Br)cccc1NC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
A mixture of 3-bromo-2-methylaniline (1.50 g, 8.06 mmol) and 6-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (1.46 g, 8.06 mmol) in toluene (40 mL) was cooled on an ice-water bath and treated portionwise with 2 M trimethylaluminum in toluene (10.1 mL, 20.2 mmol). The mixture was stirred at room temperature for 30 min, then was heated at 70° C. overnight. The mixture was cooled to 0° C., carefully treated with 1M aqueous HCl, and extracted 3 times with EtOAc. The combined organic phases were washed sequentially with saturated aqueous NaHCO3 and water, dried and concentrated. The residue was subjected to column chromatography on silica gel (120 g), eluting with EtOAc-hexanes (gradient from 5-40%), to provide 2-amino-N-(3-bromo-2-methylphenyl)-5-fluorobenzamide (0.893 g, 87% purity, 30% yield). Mass spectrum m/z 323, 325 (M+H)+. 1H NMR (400 MHz, MeOH-d4) δ 7.54 (1H, dd, J=8.03, 0.99 Hz), 7.48 (1 H, dd, J=9.68, 3.08 Hz), 7.33 (1 H, d, J=7.26 Hz), 7.16 (1 H, t, J=7.92 Hz), 7.04-7.12 (1 H, m), 6.83 (1 H, dd, J=9.02, 4.62 Hz), 2.39 (3 H, s).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]=O>N1CCCCC1.C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: O=Cc1ccccn1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(CCO)c2C1=Cc1ccccn1
Temperature: 90 °C
Yield: 45.9 %

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (80 mg, 0.45 mmol) and 2-pyridinecarboxaldehyde (60 mg, 0.56 mmol) in 1% of piperidine in ethanol (5 mL) was heated at 90° C. for 8 hours. The reaction mixture was concentrated and the residue was chromatographed on a column of silica gel. It was then triturated with ethyl acetate and hexane to give 55 mg (46%) of 4-(2-hydroxy-ethyl)-3-pyridin-2-ylmethylene-1,3-dihydro-indol-2-one.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH3:16]O>>[ClH:3].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: NCCCCCCCC(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)CCCCCCCN
Product: Cl
Temperature: 20 °C

Procedure:
0.7 cm3 of thionyl chloride is added to a solution of 1 g of 8-aminooctanoic acid in 40 cm3 of methanol at a temperature in the region of -20° C. and stirring is maintained for 12 hours at a temperature in the region of 20° C. The solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. 1.48 g of methyl 8-aminooctanoate hydrochloride is thus obtained in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](O)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3c2C1
Yield: 15.7 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 18.0 mg (0.086 mMol) 2,6-dichlorobenzoic acid, 2.4 mg (16%) of the title compound were recovered as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(=O)Cl
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CC(C)C)c(Cl)c1Cl
Temperature: 5 °C

Procedure:
A stirred mixture of 2,3-dichloroanisole (265 g., 1.50 mole) and isovaleryl chloride (200 g., 1.64 mole) in methylene chloride (1.2 1.) is cooled to 5° C. and treated with aluminum chloride (220 g., 1.64 mole) during a two-hour period. The reaction is allowed to warm to 25° C. and after 24 hours is poured into ice water (3 l.) and hydrochloric acid (600 ml.). The organic phase is washed with 10% sodium hydroxide and water and dried over magnesium sulfate. After evaporation of the solvent, the product is crystallized from hexane affording 295 g. of 2',3'-dichloro-4'-methoxyisovalerophenone which melts at 49°-54° C.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]1([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][CH:25]=[C:20]3C(C(O)=O)=[CH:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[C:20]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:17]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:18]=1)=[O:3]
Reactant: O=C(O)c1cn(-c2nccc3ccccc23)c2ncccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1cn(-c2nccc3ccccc23)c2ncccc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
0.61 cm3 (6.91 mmol) of oxalyl chloride was added, at a temperature in the region of 20° C., to 1.0 g (3.46 mmol) of 1-(isoquinolin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid in suspension in 30 cm3 of dichloromethane. After stirring at a temperature in the region of 20° C. for 2 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) and used directly in the following stage.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[CH3:6][C:7](O)([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:8].S(=O)(=O)(O)[OH:16]>C(O)(=O)C>[NH2:5][CH2:4][C:3]([NH:2][C:7]([CH3:8])([CH3:6])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:16]
Reactant: CCCCCC(C)(C)O
Reactant: N#CCN
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCC(C)(C)NC(=O)CN
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of aminoacetonitrile hydrochloride (9.25 g, 0.1 mol) and 2-methylheptan-2-ol (13.0 g, 0.1 mol) in acetic acid (60 ml) was treated with concentrated sulphuric acid (12 ml) with the temperature held at 25°-30° C. After stirring for 2 hours the mixture was pouredinto ice-water (300 ml) and washed with ether (2×200 ml). The aqueousphase was basified with 10 N sodium hydroxide solution, extracted with ether (3×200 ml) and the combined extracts were dried over magnesiumsulphate then evaporated to give 2-amino-N-(1,1-dimethylhexyl)acetamide.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1>C(O)(C)C.O>[CH2:3]([C:2]1[N:10]2[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][C:9]2=[N:8][CH:1]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC=O
Reactant: Nc1ccc(C(=O)O)cn1
Solvent: CC(C)O
Solvent: O
Product: CCCCc1cnc2ccc(C(=O)O)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To hexanal (1.02 g, 10.2 mmol) in 15 mL of isopropyl alcohol-water (4:1 v/v) was added CuCl2 (1.37 g, 10.2 mmol). The mixture was heated at 80° C. for 2.5 h, then cooled. The solids were removed by filtration and the filtrate was added to 6-aminonicotinic acid (1.35 g, 10 mmol). The mixture was stirred overnight at room temperature, then heated at reflux 32 h. After cooling, the solvents were removed under reduced pressure and MeOH was added to the residue. The resulting solid was removed by filtration and the filtrate was concentrated to dryness. MeOH was again added, and the resulting solid removed by filtration. After concentration of the filtrate, the residue was chromatographed on silica gel using MeOH-dichloromethane (33/67) to give 0.26 g of 3-butylimidazo[1,2-a]pyridine-6-carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(C)[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>C(OC(C)=O)C.Cl.COC(OC)(C)C>[CH3:8][C:7]1([CH3:12])[O:6][CH:3]([CH2:2][NH2:1])[CH2:4][O:5]1
Reactant: NCC(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: COC(C)(C)OC
Product: CC1(C)OCC(CN)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 533.6 %

Procedure:
3-Aminopropane-1,2-diol (400 mg, 4.4 mmol) was dissolved in EtOAc—HCl (20 mL). And the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo to get to the white solid. The white solid was added in 2,2-dimethoxy-propane (10 mL) and toluene-4-sulfonic acid (86 mg, 0.5 mmol) was added into the mixture. The reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was concentrated in vacuo, washed by acetone to give (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (350 mg, yield: 46%). 1HNMR (DMSO-d6, 400 MHz): δ8.08 (s, 2H), 4.32 (s, 1H), 4.05 (q, J=4.8 Hz, 1H), 3.73 (t, J=6.4 Hz, 1H), 3.00-2.78 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H)
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[S:11]1[CH2:16][CH2:15][CH:14](OS(C)(=O)=O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:14]2[CH2:15][CH2:16][S:11][CH2:12][CH2:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(F)ccc1O
Reactant: CS(=O)(=O)OC1CCSCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(F)ccc1OC1CCSCC1

Procedure:
In a manner similar to the method described in Example 128a, 5-fluoro salicylaldehyde (Aldrich) reacted with methanesulfonic acid tetrahydro-thiopyran-4-yl ester prepared in Example 130a and potassium carbonate in dimethylformamide to give a solid. MS (H+), 241.
Reaction SMILES: [CH:1]1N=CN(C(N2C=NC=C2)=O)[CH:2]=1.[Cl:13][C:14]1[CH:44]=[CH:43][C:17]([CH2:18][N:19]([C:25]([C:27]2([CH3:42])[CH2:30][CH2:29][N:28]2[C:31](=[O:41])[CH2:32][C:33]2[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=2)=[O:26])[CH2:20][CH2:21]C(O)=O)=[CH:16][CH:15]=1.[Mg+2].[Cl-].[Cl-].[C:48]([OH:54])(=O)[CH2:49][C:50]([OH:52])=[O:51].C([K])C>C1COCC1>[CH2:1]([O:52][C:50](=[O:51])[CH2:49][C:48](=[O:54])[CH2:21][CH2:20][N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:44][CH:43]=1)[C:25]([C:27]1([CH3:42])[CH2:30][CH2:29][N:28]1[C:31](=[O:41])[CH2:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:26])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCC(=O)O)Cc2ccc(Cl)cc2)c1
Reactant: O=C(O)CC(=O)O
Agent: CC[K]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of CDI (4 eq) in THF was added 3-((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-propionic acid, compound 65 (1 eq.), the mixture was stirred for 4 h at 20° C., then MgCl2 (4 eq.) and ethyl potassium malonate (5 eq.) were added. The reaction was stirred for 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with Hept/EtOAc/DCM/MeOH: 50/50/95/5 then 50/50/90/10) to afford 5-((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-3-oxo-pentanoic acid ethyl ester.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C:29](O)=[O:30])[N:19]([CH3:28])[C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[CH:12][CH:11]=1>>[CH2:1]([NH:8][C:29]([C:18]1[N:19]([CH3:28])[C:20]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:9])=[CH:15][CH:14]=2)[N:17]=1)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc(C(=O)O)n(C)c2-c2ccc(C)cc2)cc1
Reactant: NCc1ccccc1
Product: Cc1ccc(-c2nc(C(=O)NCc3ccccc3)n(C)c2-c2ccc(C)cc2)cc1

Procedure:
Using essentially the same procedure as Example 9, Step B, but using benzylamine (0.022 mL), 4,5-di-(4-methylphenyl)-1-methylimidazole-2-carboxylic acid (25 mg, 0.08 mmol) from Example 9, Step A was converted to the title compound. HPLC/MS: 396 (M+1); Rt=4.13 min.
Reaction SMILES: [OH:1][CH:2]([CH:12]1[CH:19]2[CH:15]([O:16][C:17](=[O:20])[CH2:18]2)[CH2:14][CH:13]1[CH3:21])[CH:3]=[CH:4][C:5]([CH3:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:22]([O:1][CH:2]([CH:12]1[CH:19]2[CH:15]([O:16][C:17](=[O:20])[CH2:18]2)[CH2:14][CH:13]1[CH3:21])[CH:3]=[CH:4][C:5]([CH3:10])([CH3:11])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCC(C)(C)C=CC(O)C1C(C)CC2OC(=O)CC21
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC(C)(C)C=CC(OC(C)=O)C1C(C)CC2OC(=O)CC21

Procedure:
Following the procedure of example VII, 48.9 g, of crude, optically active [3aR-[3a alpha,4alpha(1S*,2E), 5beta,6a alpha-]]-4-[1-(hydroxy)-4,4-dimethyl-2-octenyl]hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one was acetylated with 60 ml of acetic anhydride and 0.5 g of 4-dimethylaminopyridine in 400 ml of ethyl acetate. The product was crystallized from 60 ml of hexane giving 30.05 g of optically active [3aR-[3alpha,4alpha(1S*,2E),5beta,6a alpha-]]-4-[1-(acetyloxy)-4,4-dimethyl-2-octentyl]-hexahydro- 5-methyl-2H-cyclopenta[b]furan-2-one in colorless crystals with mp 83°-83.5°.
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[C:5]([NH:8][CH2:9][CH2:10][N:11]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]1[CH3:17])(=[O:7])[CH3:6].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:5]([NH:8][CH2:9][CH2:10][N:11]1[C:12]([CH3:17])=[CH:13][C:14]([S:2]([CH3:1])=[O:3])=[C:15]1[CH3:16])(=[O:7])[CH3:6]
Reactant: CS(=O)Cl
Reactant: CC(=O)NCCn1c(C)ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NCCn1c(C)cc(S(C)=O)c1C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
19.7 g (0.2 mol) of methylsulphinyl chloride are dissolved in 500 ml of methylene chloride. 36.0 g (0.2 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole and 27.6 ml (0.2 mol) of triethylamine in 500 ml of methylene chloride are added dropwise at 0° C. and the mixture is stirred at 0° C. for 45 minutes and poured onto aqueous sodium bicarbonate solution. The organic phase is separated off and discarded. The aqueous phase is concentrated and the residue is boiled up with isopropanol and, after the mixture has been concentrated, the product is chromatographed.
Reaction SMILES: CCN(CC)CC.[C:8]1([C:14]2[N:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:23][NH2:24].Cl.[CH2:26]([O:28][C:29](=[O:31])[CH3:30])[CH3:27]>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:31])[CH2:30][NH:23][NH:24][C:20]([C:17]1[CH:16]=[N:15][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:19][CH:18]=1)=[O:21])[CH3:27]
Reactant: CCOC(C)=O
Reactant: NN
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CNNC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17 %

Procedure:
Et3N (13.15 mmol) is added to a stirred solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride (5.26 mmol) and hydrazine-acetic acid ethyl ester hydrochloride (5 mmol) in DCM (30 mL) at rt, and the mixture is stirred at rt for 5 h. The mixture is quenched with water and extracted with EtOAc (60 mL). The organic layer is washed with water (20 mL) and brine (15 mL), dried, filtered and concentrated in vacuo. The residue is purified by silical gel chromatography eluting with 5-50% EtOAc in heptane to afford [N′-(2-phenyl-pyrimidine-5-carbonyl)-hydrazino]-acetic acid ethyl ester (256 mg, 16%) as a solid. MS: 301 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.35 (s, 3H), 4.20-4.40 (m, 4H), 4.56 (s, 2H), 7.54 (m, 3H), 8.53 (m, 2H), 9.24 (s, 2H).