Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:14]1[S:18][CH:17]=[C:16]([C:19]#[N:20])[CH:15]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][C:6](OCC)=[O:7])#[N:2].[BH4-].[Li+].Cl.O>C1COCC1>[C:1]([C:3]([C:14]1[S:18][CH:17]=[C:16]([C:19]#[N:20])[CH:15]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][CH2:6][OH:7])#[N:2]
Reactant: CCOC(=O)CCC(C#N)(c1cc(C#N)cs1)C(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C#N)(CCCO)c1cc(C#N)cs1

Procedure:
Ethyl 4-cyano-4-(3-cyano-5-thienyl)-5-methylhexanate (0.55 g) was dissolved in THF (10 ml), lithium borohydride (46 mg) was added, and the mixture was heated under reflux for 1.5 hours. After cooling as it was to room temperature, 1N aqueous hydrochloric acid and water were added at 0° C., and the mixture was extracted with ethyl acetate. The mixture was further washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give the title compound pale as a yellow oil (1.25 g, 47%). Further, the catalyst was filtered off, and the filtrate was evaporated. The resulting residue was purified by preparative thin layer silica gel column chromatography (hexane/ethyl acetate system), to give the title compound as a pale yellow oil (0.39 g, 83%).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1.I[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH3:9][O:10][C:11](=[O:22])[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCCC1)c1cccc([N+](=O)[O-])c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (43.3 mL of a 0.3 M stock solution, 12.99 mmol) cooled to −78° C. was treated with (3-nitro-phenyl)-acetic acid methyl ester (2.45 g, 12.56 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (32 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Iodomethylcyclopentane (2.78 g, 13.23 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (2.78 mL), and the mixture was stirred at −78° C. for 3 h. The reaction was warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (25 mL) and was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (2×25 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3-nitro-phenyl)-propionic acid methyl ester (1.63 g, 46.8%) as pale yellow oil: EI-HRMS m/e calcd for C15H19NO4 (M+) 277.1314, found 277.1317.
Reaction SMILES: N1([O:10][C:11]2[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:19]([NH:21][C:22]3[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]4[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]4)[N:23]=3)=[O:20])[C:15](=[O:17])[CH:16]=2)C2C=CC=CC=2N=N1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55]O>C(#N)C>[Cl:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[CH2:54][CH2:55][O:10][C:11]1[CH:12]=[N:13][N:14]([CH:18]([CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[C:19]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][C@@H:28]3[CH2:32][O:31][C:30]([CH3:34])([CH3:33])[O:29]3)[N:23]=2)=[O:20])[C:15](=[O:17])[CH:16]=1
Reactant: OCCc1ccccc1Cl
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(On4nnc5ccccc54)cc3=O)n2)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(OCCc4ccccc4Cl)cc3=O)n2)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (0.30 g, 0.54 mmol) in acetonitrile (10 mL, 0.055M) was treated with cesium carbonate (0.36 g, 1.10 mmol) and 2-(2-chloro-phenyl)-ethanol (86 μL, 0.65 mmol). The resulting reaction mixture was stirred at 25° C. overnight. The reaction mixture was then heated at 75° C. for 5.5-6 h. At this time, the reaction was partitioned between water and methylene chloride. The organics were dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 12 g, 50-75% ethyl acetate/hexanes) afforded 2-{4-[2-(2-chloro-phenyl)-ethoxy]-6-oxo-6H-pyridazin-1-yl}-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide (114.1 mg, 37%) as a light yellow solid as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][C:13]([C:19](Cl)=[O:20])=[CH:12]2)[CH3:8].O>N1C=CC=CC=1>[CH2:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[N:14][C:13]([C:19]([NH:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)=[O:20])=[CH:12]2)[CH3:8]
Reactant: CCc1ccc2nnc(C(=O)Cl)cc2c1
Reactant: Nc1nnn[nH]1
Solvent: O
Solvent: c1ccncc1
Product: CCc1ccc2nnc(C(=O)Nc3nnn[nH]3)cc2c1
Reaction time: 8 h

Procedure:
A solution of 5-amino-1,2,3,4-tetrazole (0.425 g.) in dry pyridine (10 ml.) was added to 6-ethylcinnolin-3-yl carbonyl chloride (1.1 g.). The resulting solution was kept at room temperature overnight, and water (50 ml.) and N-hydrochloric acid (50 ml.) were then added. The mixture was filtered, and the solid residue washed with water and crystallised from aqueous dimethylformamide to give 6-ethyl-N-(1,2,3,4-tetrazol-5-yl)cinnolin-3-yl carboxamide, m.p. over 250° C.
Reaction SMILES: C([Li])CCC.CCCCCC.[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1.[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[F:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Fc1ccc2cc[nH]c2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Prepared according to: Schlosser, M.; Ginanneschi, A.; Leroux, F. Eur. J. Org. Chem. 2006, 2956-2969. In a 500 mL round bottomed flask, THF (75 mL) was cooled to −78° C. and treated with a butyllithium solution, 1.6 M in hexane (23.12 mL, 37.0 mmol), 6-fluoroindole (5.00 g, 37.0 mmol) and triisopropylsilyl chloride (7.92 mL, 37.0 mmol). The solution was then removed from the cooling bath and warmed to RT and stirred for 1 h. The reaction mixture was concentrated on the rotovap and the crude residue was purified on the ISCO Combiflash Companion (40 g Redisep column, using a gradient of 0-10% EtOAc in hexanes) affording 6-fluoro-1-(triisopropylsilyl)-1H-indole (9.78 g, 33.6 mmol, 91% yield) as a clear, viscous colorless oil. MS (ESI, pos. ion) m/z 292.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.51 (1H, dd, J=8.4, 5.9 Hz), 7.13-7.23 (2H, m), 6.83-6.92 (1H, m), 6.59 (1H, d, J=2.3 Hz), 1.68 (3H, quin, J=7.5 Hz), 1.14 (18H, d, J=7.6 Hz).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:31]([C@@H:33]1[C@H:36](OC(=O)C)[N:35]([NH2:41])[C:34]1=[O:42])=[O:32])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C1COCC1>CC(C)=O.[OH-].[Na+]>[CH2:8]([O:15][C:16]([NH:18][C@H:19]([C:31]([C@@H:33]1[C@H:36]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:35]([NH2:41])[C:34]1=[O:42])=[O:32])[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)O[C@H]1[C@@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)OCc2ccccc2)C(=O)N1N
Reactant: Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: NN1C(=O)[C@H](C(=O)[C@H](Cc2ccc3ccccc3c2)NC(=O)OCc2ccccc2)[C@@H]1Oc1ccccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
To a solution of phenol (30 mg, 0.32 mmol) in acetone (2 ml) and 1 N NaOH (0.25 ml), (3S,4S)-3{N-benzyloxycarbonyl-β-(2-naphthyl)-L-alanyl}-amino-4-acetoxy-azetidin-2-one (95 mg, 0.2 mmol) in acetone (1 ml) and THF (2 ml) was added at 5° C. The mixture was stirred at 5° C. for 1 hr and then at room temperature for 1 hr. After removal of solvent, the residue was dissolved in ethyl acetate, washed with water, brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using ethyl acetate-hexane (1:2) as eluent and 45 mg of (3S,4S)-3-{N-benzyloxycarbonyl-β-(2-naphthyl)-L-alanyl}-amino-4-phenoxy-azetidin-2-one was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:7][S:8][CH2:9][CH2:10][NH2:11])=[N:4][S:5][CH:6]=1.[CH3:12][N:13]=[C:14]=[O:15]>>[CH3:12][NH:13][C:14]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[C:2]([Br:1])=[CH:6][S:5][N:4]=1)=[O:15]
Reactant: CN=C=O
Reactant: NCCSCc1nscc1Br
Product: CNC(=O)NCCSCc1nscc1Br

Procedure:
Reacting 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole with methyl isocyanate by the procedure of Example 24 gives the title compound.
Reaction SMILES: [Na].[CH:2]1[C:18]2[CH2:17][C@H:16]3[N:19]([CH2:21][CH2:22][C@@:8]45[C@H:15]3[CH:14]=[CH:13][C@H:11]([OH:12])[C@@H:9]4[O:10][C:6]([C:7]=25)=[C:4]([OH:5])[CH:3]=1)[CH3:20].Br[CH2:24][CH2:25][CH2:26][C:27]#[N:28]>C(O)C>[C:27]([CH2:26][CH2:25][CH2:24][O:5][C:4]1[CH:3]=[CH:2][C:18]2[CH2:17][C@H:16]3[N:19]([CH3:20])[CH2:21][CH2:22][C@:8]45[C:7]=2[C:6]=1[O:10][C@H:9]4[C@@H:11]([OH:12])[CH:13]=[CH:14][C@@H:15]35)#[N:28]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reactant: N#CCCCBr
Agent: [Na]
Solvent: CCO
Product: CN1CC[C@]23c4c5ccc(OCCCC#N)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a solution of 0.973 g of sodium dissolved in 100 ml of abs. ethanol was added 12.1 g (0.042 mol) of morphine. After heating at reflux for 1 hr, the reaction mixture was cooled to room temperature and 6.3 g of 4-bromobutyronitrile was added; then heating under reflux was resumed for 16 hr. After removal of the ethanol, the residue was dissolved in chloroform (150 ml). The chloroform solution was washed with 2 N sodium hydroxide (2 × 50 ml) and with water (50 ml). After drying, the solvent was removed in vacuo to give 14.0 g of crude 3-(3-cyanopropoxy)-7,8-didehydro-4,5 α-epoxy-17-methylmorphinan-6 α-ol. A sample of this compound was distilled, b.p. 260°-265°/0.25 mm; [α]D25 -104.09°(c 1.06, MeOH).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[CH:15]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>O1CCCC1>[CH:15]1([CH2:21][C:22]([NH:14][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]4[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=4[C:9]=3[CH:1]=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)CC1CCCCC1
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CC1CCCCC1)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 20.6 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), cyclohexylacetyl chloride (0.80 g, 6.0 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (24 mL) provided 2-cyclohexyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-acetamide (0.32 g). Mp 189-191° C.; MS m/z 312 ([M+H]+); Anal. Calcd. for C20H25NO2: C, 77.14; H, 8.09; N, 4.50; Found: C, 77.44; H, 8.08; N, 4.59.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Cl)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[C:26](=[O:34])[CH:25]=[N:24]2)=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+].CC(O)(C)C>O>[CH2:30]([N:27]1[C:26](=[O:34])[CH:25]=[N:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N:16]3[CH2:14][CH2:13][N:4]([C:5]4[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=4)[CH2:3][CH2:2]3)=[CH:22][CH:21]=2)[C:28]1=[O:29])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCn1c(=O)cnn(-c2ccc(N)cc2)c1=O
Reactant: COc1ccc(N(CCCl)CCCl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCn1c(=O)cnn(-c2ccc(N3CCN(c4ccc(OC)cc4)CC3)cc2)c1=O
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A mixture of 27.1 parts of N,N-bis(2-chloroethyl)-4-methoxybenzenamine, 29 parts of 2-(4-aminophenyl)-4-butyl-1,2,4-triazine-3,5(2H,4H)-dione, 18.4 parts of sodium hydrogen carbonate and 350 parts of 2-methyl-2-propanol was stirred overnight at reflux temperature. After cooling, 200 parts of water was added. The precipitated product was filtered off and crystallized from 4-methyl-2-pentanone. The product was filtered off and dried in vacuo at 75° C., yielding 19.8 parts (41.3%) of 4-butyl-2-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione; mp. 181.3° C. (int. 29).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)([CH3:11])[CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])C>CO.[OH-].[Na+]>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([S:12][C:5]([CH3:11])([CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[C:4]([OH:21])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(C)(CC=C(C)C)Sc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(SC(C)(CC=C(C)C)C(=O)O)cc1

Procedure:
2-(4-Methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid was prepared starting from 2-(4-methoxy-phenylsulfanyl)-2,5-dimethyl-hex-4-enoic acid ethyl ester (2.0 g, 6.4 mmol) dissolved in methanol (50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in Example 1. Yield is 1.9 g, 99% of low melting solid. MS: 280 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11][C@H:10]1[N:25]1[CH:33]=[N:32][C:31]2[C:26]1=[N:27][C:28]([CH2:49][C:50]#[N:51])=[N:29][C:30]=2[NH:34][CH2:35][CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N.[H][H]>C(O)C.[Ni]>[NH2:51][CH2:50][CH2:49][C:28]1[N:27]=[C:26]2[C:31]([N:32]=[CH:33][N:25]2[C@H:10]2[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][CH3:24])[O:11]2)=[C:30]([NH:34][CH2:35][CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[N:29]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CC#N)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CCN)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 56.7 %

Procedure:
A solution of 2-{9-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(methoxymethyl)tetrahydro-2-furanyl]-6-[(2,2-diphenylethyl)amino]-9H-purin-2-yl}acetonitrile (1.9 g, 2.6 mmol) (preparation 17) in ethanol (40 ml) saturated with ammonia gas was treated with Raney Nickel (400 mg), pressurised to 414 kPa (60 psi) with hydrogen in a sealed vessel and stirred at room temperature for 4 days. The mixture was then filtered through Arbocel (trade mark) and the residue washed with ethanol. The solvent was removed under reduced pressure from the filtrate, the residue dissolved in pentane and the solvent again removed under reduced pressure to give the title compound as a powder (1.08 g). MS: 733 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[CH:49]=[N:48][NH:47][C:44]3=[N:45][CH:46]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:41]3[CH:42]=[C:43]4[CH:49]=[N:48][NH:47][C:44]4=[N:45][CH:46]=3)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: CC1(C)OB(c2cnc3[nH]ncc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2nc(-c3cnc4[nH]ncc4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 100 °C

Procedure:
To a solution of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (51 mg, 0.095 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (28 mg, 0.123 mmol) in degassed 1,4-dioxane (250 μL) and water (25 μL) was added aqueous K2CO3 (95 μL of a 2.0 M solution) and tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.005 mmol). The reaction mixture was heated at 100° C. for 6 h, cooled and partitioned between ethyl acetate and brine. The organic layer was separated, dried over Na2SO4 and concentrated. The crude material was used without any further purification. LCMS-ESI+: calc'd for C31H34ClN4O3S: 577.2 (M+H+); Found: 577.3 (M+H+).
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([C:26]2[C:27](=[O:42])[NH:28][C:29](=[O:41])[C:30]=2[C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37](Br)[CH:38]=3)[NH:33][CH:32]=2)[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH2:19][CH2:18][CH2:17][N:16]3[CH:15]=1.O>C1(C)C=CC=CC=1.C(O)C.C([O-])(O)=O.[Na+]>[C:14]1([C:26]2[C:27](=[O:42])[NH:28][C:29](=[O:41])[C:30]=2[C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)[CH:38]=3)[NH:33][CH:32]=2)[C:24]2=[C:25]3[C:20](=[CH:21][CH:22]=[CH:23]2)[CH2:19][CH2:18][CH2:17][N:16]3[CH:15]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(Br)cc12
Reactant: OB(O)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccc(-c3cccc4ccccc34)cc12
Temperature: 10 °C
Yield: 70.9 %

Procedure:
A mixture of 1-naphthyl boronic acid (41 mg, 0.24 mmol), 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(5-bromo-1H-indol-3-yl)pyrrole-2,5-dione (88 mg, 0.2 mmol) (prepared as in Example 24), tetrakistriphenylphosphine palladium (5 mol %) in toluene (4 ml), ethanol (4 ml), saturated NaHCO3 (1 ml), and water (2 ml) was heated at 10° C. under nitrogen for 5 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate (3×15 ml) and concentrated. The residue was purified by silica gel chromatography, eluting with ethyl acetate/hexanes (1:4) to afford 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(5-1-naphthyl-1H-indol-3-yl)pyrrole-2,5-dione as a bright red solid (70 mg, 71%). 1H NMR (CD3OD) δ: 1.80-1.92 (m, 2H), 2.72-2.80 (t, J=6.0 Hz, 2H), 3.94-3.99 (t, J=6.0 Hz, 2H), 6.50-6.58 (m, 3H), 6.66 (s, 1H), 6.72 (m, 1H), 6.98 (dd, J=8.4 Hz, J′=2.0 Hz, 1H), 7.00-7.50 (m, 2H), 7.28 (dd, J=6.8 Hz, J′=8.4 Hz, 1H), 7.38-7.43 (m, 2H), 7.61 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.97 (s, 1H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH2:40])=[CH:33][C:32]=2[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=O)C.C(OC([N:55]1[CH2:60][CH2:59][N:58]([C:61](=[O:68])[C:62]([C:65](O)=[O:66])([CH3:64])[CH3:63])[CH2:57][CH2:56]1)=O)C1C=CC=CC=1.C(OC(NCC(O)=O)=O)C1C=CC=CC=1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][NH:40][C:65](=[O:66])[C:62]([CH3:63])([C:61]([N:58]4[CH2:59][CH2:60][NH:55][CH2:56][CH2:57]4)=[O:68])[CH3:64])=[CH:33][C:32]=3[CH3:41])=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCN)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)(C(=O)O)C(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C(O)CNC(=O)OCc1ccccc1
Product: Cc1cc(OCCNC(=O)C(C)(C)C(=O)N2CCNCC2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 13 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-aminoethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 1-benzyloxycarbonyl-4-[2-carboxy-2-(methyl)propionyl]piperazine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-aminopropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole and 2-benzyloxycarbonylaminoacetic acid, respectively.
Reaction SMILES: O[CH:2]([CH3:15])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11][C:12]([OH:14])=[O:13].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(#N)C>[C:12]1(=[O:14])[O:13][CH:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH:9]=[CH:10][CH2:11]1
Reactant: CC(O)CCC/C=C\C/C=C\CC(=O)O
Agent: CC1CCC/C=C\C/C=C\CC(=O)O1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1CCCC=CCC=CCC(=O)O1

Procedure:
A solution of hydroxy-acid 14 (0.64 g, 3.1 mmol) and dry triethylamine (2.42 g, 24 mmol) in dry acetonitrile (200 mL) was added over 20 hr via a fixed-rate addition funnel and a high dilution head to a refluxing solution of 2-chloro-N-methyl-pyridinium iodide (3.18 g, 12.4 mmol) in dry acetonitrile (200 mL), under argon. The resulting solution was refluxed a further 2 hr, cooled, and concentrated in vacuo. The residue was taken up in pentane (50 mL) and washed with water (50 mL). The aqueous phase was extracted twice more with pentane (25 mL), and the combined pentane extracts were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was flash chromatographed (hexane:EtOAc, 40:1), yielding 45 mg (7.5% yield) of macrolide II. ##STR3##
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:2].[BH4-].[Na+].[OH2:28]>O1CCCC1.[OH-].[Na+]>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][C:19]([OH:28])([CH3:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[NH2:2]
Reactant: CCCCCC(C)=CCCC(CCCCCCC(=O)OCC)C(N)=O
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCC(C)(O)CCCC(CCCCCCC(=O)OCC)C(N)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Mercuric acetate (3.8 g., 0.012 mole) is dissolved in water (12 ml.) and tetrahydrofuran (20 ml.) is added to give a suspension of a yellow solid. Then, ethyl 8-carbamoyl-12-methyl-11-heptadecenoate (4.2 g., 0.012 mole) in tetrahydrofuran (20 ml.) is added, and the mixture stirred at room temperature for 24 hours. After 6 hours, the yellow suspended solid has disappeared and a cloudy solution results. To the solution is added 3M sodium hydroxide solution (12 ml.), followed by 0.5M sodium borohydride solution in 3M sodium hydroxide (12 ml.). Liquids are decanted from the precipitated mercury. The organic layer is taken up in ether, washed with three portions of water and dried over sodium sulfate. Evaporation of the ether leaves 4.0 g. of ethyl 8-carbamoyl-12-hydroxy-12-methylheptadecanoate which is used in the next step without further purification.