Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].O.C[O:5][C:6](=[O:43])[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21]([CH2:41][CH3:42])([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH2:38][CH3:39])[CH:32]([OH:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:26]([CH3:40])[CH:25]=3)[CH2:22][CH3:23])[CH:17]=2)[CH:12]=1)=[O:10].CO>C1COCC1>[CH2:22]([C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([C:9]([NH:8][CH2:7][C:6]([OH:43])=[O:5])=[O:10])[CH:20]=[CH:19]2)([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH2:38][CH3:39])[CH:32]([OH:37])[C:33]([CH3:36])([CH3:34])[CH3:35])=[C:26]([CH3:40])[CH:25]=1)[CH2:41][CH3:42])[CH3:23]
Reactant: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)NCC(=O)OC)ccc3c2)cc1C)C(O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)NCC(=O)O)ccc3c2)cc1C)C(O)C(C)(C)C
Yield: 85.3 %

Procedure:
Add 2.5 M LiOH/H2O (0.82 ml, 2.04 mmol) to diastereomeric isomer pair 1 of 2-[6-{1-ethyl-1-[4-(1-ethyl-2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-naphthalene-2-carbonylamino]acetic acid methyl ester (373 mg, 0.681 mmol) in THF (3 ml), and MeOH (1.5 ml). Stir the reaction for 14 h; then partition the reaction mixture between Et2O and 1N HCl. Dry the organic layer with MgSO4, concentrate and triturate the residue with CH2Cl2/MeOH/hexanes to give the title compound as a white solid (310 mg, 85%). 1NMR (400 MHz, CDCl3) δ ppm: 0.64 (t, J=7.2 Hz, 6H), 0.93 (t, J=8.0 Hz, 3H), 0.93 (s, 9H), 1.68 (m, 1H), 1.81 (m, 1H), 2.11 (s, 3H), 2.15 (q, 4H), 3.28 (s, 1H), 4.27 (dd, J=5.2, 3.6 Hz, 1H), 4.35 (d, J=4.8 Hz, 2H), 6.63 (d, J=8.0 Hz, 1H), 6.83 (t, J=4.8 Hz, 1H), 6.89 (s, 1H), 6.93 (dd, J=6.4, 2.2 Hz, 1H), 7.18 (dd, J=7.2, 1.6 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.88 (m, 3H), 8.27 (s, 1H). High Res. ES-MS: 556.3046; calc. for C33H43NO5+Na: 556.3040.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([OH:15])=[O:14].FCCO.[CH2:21]([N:24]1[CH2:28][C:27](=[O:29])[N:26]([CH2:30]O)[C:25]1=[O:32])[C:22]#[CH:23]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:12])[O:8][CH2:9][CH2:10][F:11])[C@H:3]1[C:13]([O:15][CH2:30][N:26]1[C:27](=[O:29])[CH2:28][N:24]([CH2:21][C:22]#[CH:23])[C:25]1=[O:32])=[O:14]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)OCCF
Reactant: C#CCN1CC(=O)N(CO)C1=O
Agent: OCCF
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C\C(=O)OCCF)C2(C)C)C1=O

Procedure:
Using the procedure of Step F of Example 9, (1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2-fluoroethoxy)-1-propenyl]cyclopropane-carboxylic acid prepared as in Example 21 except 2-fluoroethanol was used and (3-propargyl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain (3-propargyl-2,5-dioxo-1-imidazolidinyl)-methyl(1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(2-fluoroethoxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+18°±2° (c=1% in CHCl3)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[C:23]#[N:24])=[N:9]S(C(C)(C)C)=O)[CH:7]=1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C:8]2([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=3)[C:16]3[C:17](=[C:18]([F:22])[CH:19]=[CH:20][CH:21]=3)[C:23]([NH2:24])=[N:9]2)[CH:7]=1
Reactant: CC(C)(C)S(=O)N=C(c1cc(Br)ccc1F)c1cccc(F)c1C#N
Reactant: Cc1cc(Br)ccn1
Product: Cc1cc(C2(c3cc(Br)ccc3F)N=C(N)c3c(F)cccc32)ccn1
Yield: 15 %

Procedure:
The title compound was synthesized as described for Example 14i in 15% yield, starting from N-((5-bromo-2-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (100 mg, 0.24 mmol) and 4-bromo-2-methylpyridine (44.5 mg, 0.26 mmol). Purification was achieved by preparative HPLC.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:19]1([C:2]2[C:3]([C:8]3[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=3)=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)Cc1ccc(-c2nccnc2Cl)cc1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(-c2nccnc2C2CC2)cc1
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of 0.15 g (0.57 mmol) of methyl [4-(3-chloropyrazin-2-yl)phenyl]acetate acid in 3.0 mL of toluene and 0.15 mL of water were added 63.8 mg (0.74 mmol) of cyclopropyl boronic acid, 16 mg (0.06 mmol) of tricyclohexylphosphine, 7.8 mg (0.009 mmol) of Pd2(dba)3, and 0.42 g (2.0 mmol) of potassium phosphate. The resulting suspension was degassed for 10 minutes. After 1 h in the microwave at 140° C., the reaction mixture was cooled, diluted with CH2Cl2, wash three times with water, and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-40% EtOAc in hexanes) afforded 0.10 g (65%) methyl [4-(3-cyclopropylpyrazin-2-yl)phenyl]acetate. 1H NMR (CDCl3, 400 MHz) δ 8.35 (m, 2H); 7.68 (d, J=8.06 Hz, 2H); 7.41 (d, J=8.06 Hz, 2H); 3.72 (s, 3H); 3.71 (s, 2H); 2.22 (m, 1H); 1.19 (m, 2H); 0.99 (m, 2H). ES-MS M+1=269.1.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][C@@H:4]1[C@H:7]([CH3:8])[N:6]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[C:5]1=[O:16].[OH-].[Na+].S(=O)(=O)(O)[O-:21].[Na+]>COCCOC>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][NH:6][C@@H:7]([CH3:8])[C@@H:4]([CH2:3][CH:2]([CH3:17])[CH3:1])[C:5]([OH:21])=[O:16]
Reactant: O=S(=O)([O-])O
Reactant: CC(C)C[C@H]1C(=O)N(OC2CCCCO2)[C@H]1C
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CC(C)C[C@@H](C(=O)O)[C@H](C)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
(3R,4S)-3-(2-Methyl-1-propyl)-4-methyl-1-(2-tetrahydropyranyloxy)azetidin-2-one (3.5 g, 14.5 mmol) in 30 mL of ethylene glycol dimethyl ether is treated with 20 mL of 2.5 M aqueous sodium hydroxide solution. The mixture is stirred at 25° C. for 16 h and is then brought to pH 3 by addition of saturated aqueous sodium bisulfate solution. The mixture is extracted with ether and the organics are dried over magnesium sulfate and concentrated under reduced pressure to give 3.2 g (84%) of (2R,3S)-3-(2-tetrahydropyranyloxyamino)-2-(2-methyl-1-propyl)butanoic acid as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]4[N:21]=[CH:20][N:19]=[C:18]([C:22]([O:24]CC)=[O:23])[CH:17]=4)[CH:12]=3)[CH2:7]2)[C:5](=[O:27])[NH:4][C:3]1=[O:28].[OH-].[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]2([CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:15][C:16]4[N:21]=[CH:20][N:19]=[C:18]([C:22]([OH:24])=[O:23])[CH:17]=4)[CH:12]=3)[CH2:7]2)[C:5](=[O:27])[NH:4][C:3]1=[O:28]
Reactant: CCOC(=O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)NC(=O)N2C)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1C(=O)NC(=O)C12Cc1ccc(Nc3cc(C(=O)O)ncn3)cc1C2

Procedure:
140 mg (0.37 mmol) ethyl 6-(3-methyl-2,5-dioxo-1′,3′-dihydrospiro[imidazolidin-4,2′-inden]-5′-ylamino)pyrimidine-4-carboxylate, 5 mL ethanol and 1 mL (1.0 mmol) of a 1M NaOH solution were stirred for 2 h at RT. The reaction mixture was combined with 1 mL of a 1M hydrochloric acid solution and the ethanol was eliminated i.vac. The aqueous residue was cooled and the precipitated product was suction filtered, washed with water and dried.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:7][CH2:8]Cl)[CH2:5][CH3:6])[CH3:3].C[O-].[Na+].C(=O)([O-])[O-].[K+].[K+].[C:19]1([CH:26]=[CH:25][CH:24]=[C:22]([SH:23])[CH:21]=1)[SH:20]>CO.O.C1(C)C(C)=CC=CC=1>[CH2:2]([N:4]([CH2:7][CH2:8][S:20][C:19]1[CH:21]=[C:22]([SH:23])[CH:24]=[CH:25][CH:26]=1)[CH2:5][CH3:6])[CH3:3]
Reactant: CCN(CC)CCCl
Reactant: Sc1cccc(S)c1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Solvent: CO
Product: CCN(CC)CCSc1cccc(S)c1

Procedure:
A solution of 1.72 g of diethylaminoethyl chloride hydrochloride and 0.54 g of sodium methoxide in 10 cc of methanol and a solution of 2.09 g of potassium carbonate in 10 cc of water are added to 1.42 g of dithioresorcin. After the addition of 10 cc of xylene, the mixture is boiled at reflux for 8 hours. The reaction mixture is subsequently diluted with water and extracted thrice with ethyl acetate. 10% acetic acid is subsequently added to the water phase, until the oily precipitation is complete, extraction is again effected thrice with ethyl acetate, and the ethyl acetate solution is concentrated by evaporation after drying over magnesium sulphate. Bulb tube distillation (bath temperature 135° at 0.5 mm Hg) yields the product as colourless oil which rapidly oxidizes in the air.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][C@@H:16]4[CH2:19][N:20]([CH3:22])[CH2:21][C@H:15]34)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:23]1[NH:24][C:25](=[O:29])[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>N1C2C(=CC=CC=2)C=CC=1.CCCCCC.[Cu]>[CH3:22][N:20]1[CH2:19][C@@H:16]2[C@@H:15]([N:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:24]5[C:25](=[O:29])[CH:26]=[CH:27][CH:28]=[N:23]5)=[CH:3][CH:4]=4)=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:21]1
Reactant: O=c1cccn[nH]1
Reactant: CN1C[C@H]2CCN(c3ccc(-c4ccc(Br)cc4)cc3)[C@H]2C1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CN1C[C@H]2CCN(c3ccc(-c4ccc(-n5ncccc5=O)cc4)cc3)[C@H]2C1
Temperature: 150 °C

Procedure:
The product of Example 1A (4.54 g, 12.6 mmole), 3(2H)-pyridazinone (2.41 g, 25.2 mmole), copper powder (1.60 g, 25.2 mmole) and potassium carbonate (5.21 g, 37.7 mmole) were dissolved in 63 ml of quinoline and heated at 150° C. under N2 for 48 hours. The mixture was cooled to room temperature, diluted with hexane (15 ml) and filtered through a CELITE filter (CELITE is a registered trademark of Johns-Manville Corporation of Denver, Colo.). The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluting first with diethyl ether, followed by dichloromethane, then elution with a mixture of 5% MeOH in dichloromethane) to provide the title compound, 2-{4′-[(3aR,6aR)-5-methylhexahydropyrrolo [3,4-b]pyrrol-1(2H)-yl]-1,1′-biphenyl-4-yl}pyridazin-3(2H)-one. 1H NMR (300 MHz, CDCl3) δ ppm 7.91 (dd, J=3.73, 1.70 Hz, 1 H) 7.61-7.65 (m, 4 H) 7.51 (d, J=8.48 Hz, 2 H) 7.25 (dd, dd, J=9.40, 4.07 Hz, 1 H) 7.07 (dd, J=9.49, 1.70 Hz, 1 H) 6.64 (d, J=8.81 Hz, 2 H) 4.19-4.27 (m, 1 H) 3.54-3.64 (m, 1 H) 3.28-3.38 (m, 1 H) 3.00-3.11 (m, 1 H) 2.56-2.85 (m, 4 H) 2.40 (s, 3 H) 2.10-2.29 (m, 1 H) 1.89-2.05 (m, J=6.78 Hz, 1 H); MS (M+H)+=373. The solid (3aR,6aR)-2-[4′-(5-methyl-hexahydro-pyrrolo [3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one obtained showed a melting range of 204-207° C. (dec.).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH3:4][C:3]1([CH3:5])[S:6][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: O=Cc1ccccc1
Solvent: O
Product: CC1(C)SC(c2ccccc2)N[C@H]1C(=O)O
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
A 250 mL flask was charged with 20 mL of water and 2.0 g (13.4 mmol) of D-penicillamine. To the resulting colorless solution was added 1.4 g (13.3 mmol) of benzaldehyde dropwise over 2 minutes. The resulting suspension was stirred vigorously for 30 minutes and allowed to stand at room temperature overnight. The solids thus obtained were collected by filtration to yield 3.0 g (12.6 mmol) of the title thiazolidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12]>N1C=CC=CC=1.[Cu-]=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:4]1[CH:3]=[CH:2][CH:10]=[CH:9][C:12]=1[C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:5]2
Reactant: CCOC(C)=O
Reactant: Cc1ccc2[nH]ccc2c1
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: CCOC(=O)c1ccccc1-n1ccc2cc(C)ccc21
Temperature: 120 °C

Procedure:
5-Methylindole (730.6 mg, 5.57 mmol, 1.0 eq.) was combined with the title C compound of Example 1 (3.189 g, 13.9 mmole, 2.5 eq.) and copper(I)oxide (797 mg, 5.57 mmol, 1.0 eq.) in pyridine (5.6 ml, 1M). The reaction was heated at 120° C. for 3 hours, cooled to room temperature, diluted with ethyl acetate and filtered through celite. The filtrate was washed twice with water, twice with aqueous 1N hydrochloric acid, and once with aqueous saturated sodium hydrogen carbonate. The organic phase was then dried over sodium sulfate, filtered through magnesium sulfate and concentrated. The residue was chromatographed on silica gel (50 g) eluting with hexane:ether (40:1) followed by (20:1) to give 848 mg of the title A compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>ClCCl>[CH2:26]([O:25][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C@@H:10]1[CH3:14])=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C

Procedure:
To a solution of 1.50 g (S)-4-N-Boc-2-methyl-piperazine in 10 ml dichloromethane were added at 0° C. 2.29 ml triethylamine and 0.72 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation of the solvent was used in the subsequent reaction.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[C@@H:18]([CH2:29][N:30]=[N+:31]=[N-:32])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)C.C[O-].[Na+]>CO>[N:30]([CH2:29][C@H:18]1[O:17][C@H:6]([S:7][CH2:8][CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@@H:5]([OH:4])[C@@H:20]([OH:21])[C@@H:19]1[OH:25])=[N+:31]=[N-:32]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](SCC=Cc2ccccc2)O[C@H](CN=[N+]=[N-])[C@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NC[C@H]1O[C@H](SCC=Cc2ccccc2)[C@@H](O)[C@@H](O)[C@@H]1O
Yield: 78.1 %

Procedure:
A solution of 12 (4.4 g) in dry methanol (60 ml) is deacetylated with sodium methoxide (0.5 g). The product is isolated in the normal manner and purified by column chromatography (CHCl3 --MeOH--H2O, 95:5:5, v/v) to give 13 as an oil (2.5 g, 78%): [α]D27 +220±0.9° (C 1.06 methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:4][C:3]=1[CH:18]=O.[CH3:20][NH:21][CH2:22][CH2:23][C:24]#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:24]([CH2:23][CH2:22][N:21]([CH2:18][C:3]1[CH:4]=[C:5]([C:8]#[C:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:6]=[CH:7][C:2]=1[F:1])[CH3:20])#[N:25]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(C=O)c2)c1
Reactant: CNCCC#N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN(CCC#N)Cc1cc(C#Cc2cncc(C#N)c2)ccc1F
Reaction time: 5.5 h
Yield: 43 %

Procedure:
Dissolve 5-(4-fluoro-3-formylphenylethynyl)nicotinonitrile, (prepared as described in PREPARATION 38) (100 mg, 0.40 mmol) in dichloroethane (2 mL) and treat with N-methyl-β-alaninenitrile (0.041 mL, 0.44 mmol) and sodium triacetoxyborohydride (110 mg, 0.52 mmol). After stirring for 5.5 h, quench with water (2 mL), dilute with dichloromethane and extract three times with 0.5 N hydrochloric acid, but thin layer chromatography shows some product still remaining in the organic phase. Add 1 N sodium hydroxide to the aqueous layer until it is basic then extract twice with ethyl acetate. Combine the dichloromethane layer with the ethyl acetate extracts and wash with an aqueous saturated solution of sodium chloride, dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 90:10 to 80:20 dichloromethane:ethyl acetate, to give the title compound as a white crystalline solid (55 mg, 43%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[CH:18]=O)[CH:4]=[CH2:5].[CH2:20]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[CH2:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][C:8]=1[CH:18]=[CH2:20])[CH:4]=[CH2:5]
Reactant: C=CCOc1ccc(C(=O)OCC)cc1C=O
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(C(=O)OCC)cc1C=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a stirred suspension of sodium hydride [588 mg (60% oil dispersion), 15 mmol), which had been previously washed with pentane (3×), in THF (30 mL) in a 0° C. ice bath is added methyl triphenylphosphonium bromide (4.6 g, 13 mmol). The suspension is allowed to warm to rt and stir for 30 min. A solution of ethyl 4-(allyloxy)-3-formylbenzoate (2.3 g, 9.8 mmol) in THF (10 mL) is added via canula. The mixture is stirred at rt 2 h. The mixture is diluted with EtOAc and washed with brine. The organic layer is dried of MgSO4, filtered and concentrated in vacuo to a yellow residue. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (95:5) gives 1.8 g (79%) of ethyl 4-(allyloxy)-3-vinylbenzoate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 8.2, 7.9, 7.1, 6.9, 6.1, 5.9, 5.5, 5.3, 4.7, 4.4, 1.4.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][N:10]1C(=O)C2=CC=CC=C2C1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>ClCCl>[C:1]([O:5][C:6]([CH2:8][O:9][NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)CON
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
In 1.35 l of dichloromethane is dissolved 37.4 g (0.135 mole) of N-(tert-butoxycarbonylmethoxy) phthalimide, and 9.21 ml (0.189 mole) of hydrazine hydrate is added dropwise to the solution over the period of 10 minutes, followed by stirring at room temperature for 2 hours. 3.95 ml (0.081 mole) of hydrazine hydrate is furthermore added, followed by stirring for further 1.5 hours. The reaction solution is filtered, and the filtrate is washed with 300 ml of 2N ammonium water and aqueous sodium chloride solution successively, and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure to give 18.95 g (95.4%) of O-(tert-butoxycarbonylmethyl)hydroxylamine as a yellow oily product.
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11]O)[C@@H:8]([OH:13])[C@H:7]2[OH:14])[C:4]([NH2:15])=[C:3]([C:16]([NH2:18])=[O:17])[N:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CO>[NH2:15][C:4]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][Cl:39])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[CH:1]=[N:2][C:3]=1[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: ClC(Cl)(Cl)Cl
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: NC(=O)c1ncn([C@@H]2O[C@H](CCl)[C@@H](O)[C@H]2O)c1N

Procedure:
AICA riboside (1.00 g), triphenylphosphine (3.05 g) and carbon tetrachloride (1.15 ml) were stirred in dimethyl formamide (38 ml) at room temperature for 3 hours. The solution was diluted with methanol (15 ml), then concentrated under reduced pressure. The resulting yellow tar was chromatographed on silica gel, eluting with 4:1 methylene chloride:methanol. The like fractions were combined and concentrated under reduced pressure to afford a purple foam. The presence of triphenylphosphine oxide, as determined by 1H NMR, necessitated a second chromotographic step as above. Yield was 0.43 g of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][C@H:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][NH:10][CH2:9][C@H:8]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)N1CC[C@@H](Oc2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Clc1ccc(O[C@@H]2CCNC[C@H]2c2ccccc2)cc1

Procedure:
A mixture of 8.78 g of trans-4-(4-chlorophenoxy)-1-ethoxycarbonyl-3-phenylpiperidine, 64 ml of 20% aqueous NaOH solution and 125 ml of absolute ethanol is refluxed for 18 hours under nitrogen. The ethanol is then removed in vacuo and the aqueous residue is partitioned between dichloromethane and distilled water. The aqueous phase is extracted with dichloromethane, and the combined organic extracts are then washed with water, saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and concentrated in vacuo to afford a solid which is recrystallized from cyclohexane to yield trans-4-(4-chlorophenoxy)-3-phenylpiperidine, mp 101.5°-103° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CN)CC1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(CNC2CCCC2)CC1

Procedure:
Reaction of 1-aminomethyl-cyclopropanecarboxylic acid ethyl ester with cyclopentanone, sodium acetate and sodium triacetoxyborohydride in DCM gave 1-cyclopentylaminomethyl-cyclopropanecarboxylic acid ethyl ester
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:11]=2)=[CH:8][N:9]=1)=O.[BH4-].[Na+]>CO.O1CCCC1>[CH:22]1([CH2:21][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:10]([C:7]3[S:6][C:5]([CH2:3][OH:2])=[N:9][CH:8]=3)=[CH:11]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ncc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc2c(-c3cnc(CO)s3)cn(CC3CCCCC3)c12
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazole-2-carboxylic acid methyl ester (418 mg, 1.09 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml) was added sodium borohydride (83 mg, 2.18 mmol) portionwise over 2 minutes. The reaction was stirred for a further 1 h and then quenched with aqueous hydrochloric acid (1M; 10 ml). The mixture was poured into a separating funnel, diluted with dichloromethane (50 ml) and washed with water (20 ml). The combined organic layers were dried, filtered and the solvent removed in vacuo to leave a yellow oil. The oil was purified by flash column chromatography using 50-100% (v/v) diethyl ether in heptane to give [5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazol-2-yl]-methanol (308 mg, 0.86 mmol) as an off-white foam.