Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:17]([O:19]C)=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:17]([OH:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCN(Cc1cc(C)cc(C(=O)OC)c1)C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(Cc1cc(C)cc(C(=O)O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-{[(tert-butoxycarbonyl)(butyl)amino]methyl}-5-methylbenzoate (70 mg, 0.21 mmol) in methanol (2 mL), tetrahydrofuran (1 mL), and water (1 mL) is added lithium hydroxide (88 mg, 2.1 mmol), and the reaction mixture stirred at room temperature for 2 h. The reaction mixture is concentrated under reduced pressure, dissolved in methylene chloride, filtered, and the filtrate concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].C([Li])CCC.[CH3:13][C:14]([CH3:16])=[O:15]>O1CCCC1.CCOCC.CCCCC>[CH2:1]([O:3][C:4](=[O:7])[C:5]#[C:6][C:14]([OH:15])([CH3:16])[CH3:13])[CH3:2]
Reactant: CC(C)=O
Reactant: C#CC(=O)OCC
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(C)(C)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.9 %

Procedure:
To a stirred solution of propynoic acid ethyl ester (20 mL, 197 mmol) in a mixture of 300 mL tetrahydrofuran:ether:pentane (4:1:1 by volume) cooled in a dry ice/isopropanol bath was added n-butyllithium (79 mL, 197 mmol, 2.5 M in hexanes) dropwise. After 15 minutes, anhydrous acetone (13.1 mL, 197 mmol) was slowly added. The reaction was kept below −78° C. for 8 h and quenched with an aqueous ammonium chloride solution, and the resulting mixture was stirred for 5 min. The reaction was warmed up to room temperature and extracted repeatedly with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo, and the residue was purified via silica gel column chromatography (0-15% ethyl acetate in heptane) to give the title compound (10.75 g, 68.8 mmol) as a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(O)(O)O.[OH-].[Na+]>O>[CH2:9]([NH:16][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccncc1
Agent: OP(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CNCc2ccncc2)cc1
Yield: 74 %

Procedure:
To the imine from pyridine-4-carboxaldehyde and benzylamine (20 g; 0.1 mole) was added phosphorous acid (8.4 g; 0.1 mole) and the mixture heated at 110°-130° for 11/2 hours. After cooling to 90° water (150 ml) was added. The aqueous solution was basified with NaOH and extracted with benzene (3×100 ml). Evaporation of the solvent gave the N-benzyl(4-pyridyl) methylamine 14.9 g (74%). Nmr measurements, 1H and 13C, confirmed the structural assignment.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8](=[O:36])[C:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:13]([C:24](=O)[CH2:25][S:26](=[O:32])(=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])=[C:12]([CH3:34])[NH:11][C:10]=1[CH3:35])[CH2:2][CH3:3].[BH4-].[Na+].C(Cl)Cl.C(OCC)(=O)C>C(O)C.CN(C)C=O>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8](=[O:36])[C:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:13](/[CH:24]=[CH:25]/[S:26](=[O:31])(=[O:32])[NH:27][CH:28]([CH3:30])[CH3:29])=[C:12]([CH3:34])[NH:11][C:10]=1[CH3:35])[CH2:2][CH3:3]
Reactant: CCCOCCOC(=O)C1=C(C)NC(C)=C(C(=O)CS(=O)(=O)NC(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCOCCOC(=O)C1=C(C)NC(C)=C(/C=C/S(=O)(=O)NC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 88.4 %

Procedure:
Analogously to Example 18, 1.05 g of 1,4-dihydro-5-[(isopropylsulfamoyl)acetyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid 2-propoxyethyl ester were treated with 0.08 g of sodium borohydride in a mixture of 10 ml of ethanol and 2 ml of dimethylformamide. After chromatography with methylene chloride/ethyl acetate (4:1) as the elution agent there was obtained 0.90 g of 1,4-dihydro-5-[(E)-2-(isopropylsulfamoyl)vinyl]-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid 2-propoxyethyl ester in the form of yellow crystals, m.p. 152°-154°.
Reaction SMILES: Cl[CH2:2]Cl.C[Li].[Cl:6][C:7]1[CH:8]=[C:9]([C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1)[CH:10]=[O:11].O>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH3:2])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1
Reactant: ClCCl
Reactant: O=Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li]C
Solvent: O
Solvent: CCOCC
Product: CC(O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: -50 °C
Yield: 99.7 %

Procedure:
An oven dried 250 mL 3 neck r.b.f. equipped with an internal thermometer was charged with diethyl ether (180 mL) and titanium tetrachloride, 1.0 M in dichloromethane (20.5 mL, 20.5 mmoles) under an Argon atmosphere. The solution was cooled in a CO2(a)/acetone −78° C. bath and methyl lithium, 1.6 M in diethyl ether (12.8 mL, 20.5 mmoles) was added via a syringe at a rate such that the internal temperature was </=−50° C. The resultant anion solution was stirred at −50° C. for 1 hour, at which time 2-chloro-5-nitroisonicotinaldehyde (2.54 g, 13.66 mmoles) in diethyl ether (16+4 mL) was added via syringe with the internal temp </=−50° C. After stirring for an additional hour at −50° C., the reaction was poured into H2O (500 mL), and after mixing two light yellow layers formed. Diethyl ether was added (500 mL), the layers were separated, and the organic was washed with H2O (250 mL), with NaCl(sat.) (250 mL), dried over MgSO4, filtered and concentrated yielding 1-(2-chloro-5-nitropyridin-4-yl)ethanol (2.76 g, 100% yield). LCMS (m/z): 203.0 (MH+); LC Rt=2.42 min. 1H NMR (CDCl3): δ 8.99 (s, 1H), 7.88 (s, 1H), 5.52 (m, 1H), 1.56 (d, J=9.0, 3H).
Reaction SMILES: C(OC[N:10]1[C:15](=[O:16])[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:28][CH:27]=2)[CH3:22])=[C:13]([Cl:37])[CH:12]=[N:11]1)C1C=CC=CC=1.B(Br)(Br)Br.CO.O>C1C=CC=CC=1>[Cl:37][C:13]1[CH:12]=[N:11][NH:10][C:15](=[O:16])[C:14]=1[NH:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:23][CH2:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:30][CH:31]=1)[CH3:22]
Reactant: CN(CCCNc1c(Cl)cnn(COCc2ccccc2)c1=O)CCOc1ccc(NS(C)(=O)=O)cc1
Agent: BrB(Br)Br
Solvent: c1ccccc1
Solvent: CO
Solvent: O
Product: CN(CCCNc1c(Cl)cn[nH]c1=O)CCOc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
2.69 g (4.88 mmoles) of the compound of Example 44 are dissolved in 53 ml of anhydrous benzene. 2.92 ml of boron tribromide are dropped to the solution so that the temperature of the reaction mixture should not exceed 20° C. The suspension thus obtained is stirred at room temperature for half an hour. Then 40 ml of methanol are dropped under stirring and cooling with icy water at such a rate that the inner temperature should not exceed 25° C. The reaction mixture is evaporated, the residue is boiled with 68 ml of distilled water for 1 hour, the solution is cooled, diluted with 100 ml of distilled water, the pH is adjusted with solid potassium hydrogen carbonate to neutral and the solution is extracted with chloroform. The organic phase is dried and evaporated, then the residue is purified by column chromatography. Thus 1.01 g (48%) of the desired compound are obtained. Rf =0.45. Its monohydrochloride salt melts at 181°-183° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:15][O:16][C:17]=3[CH:18]3[CH2:20][CH2:19]3)=[N:11][N:12]=2)=[C:4]([O:27][CH3:28])[CH:3]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:18]1([C:17]2[O:16][N:15]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:13]=2[C:10]2[O:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:3][C:4]=3[O:27][CH3:28])=[N:12][N:11]=2)[CH2:20][CH2:19]1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Reactant: C1COCCN1
Product: COc1cc(N2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C2CC2)o1
Yield: 59 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.53 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using morpholine instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=60:20:20 to 0:80:20, 138 mg, 59%) which was obtained as a white solid. MS: m/e=445.3 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([C:7]([C:17]2[CH:22]=[C:21]([I:23])[C:20]([O-:24])=[C:19]([I:25])[CH:18]=2)=[C:8]2[CH:14]=[C:13]([I:15])[C:11](=[O:12])[C:10]([I:16])=[CH:9]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+].[C:31]([C:33]1[CH:34]=[C:35]([CH:42]=[CH:43][CH:44]=1)[CH2:36][C@@H:37]([C:39]([OH:41])=O)[NH2:38])#[N:32].[CH2:45]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:46].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH:1]1[CH:6]=[C:5]([C:7]([C:8]2[CH:9]=[C:10]([I:16])[C:11]([O-:12])=[C:13]([I:15])[CH:14]=2)=[C:17]2[CH:18]=[C:19]([I:25])[C:20](=[O:24])[C:21]([I:23])=[CH:22]2)[C:4]([C:26]([O-:28])=[O:27])=[CH:3][CH:2]=1.[Na+:29].[Na+:29].[CH2:45]([O:47][C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:39](=[O:41])[C@H:37]([CH2:36][C:35]2[CH:42]=[CH:43][CH:44]=[C:33]([C:31]#[N:32])[CH:34]=2)[NH2:38])[CH2:54][CH2:55]1)=[O:49])[CH3:46]
Reactant: N#Cc1cccc(C[C@H](N)C(=O)O)c1
Reactant: CCOC(=O)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C(I)=CC(=C(c2cc(I)c([O-])c(I)c2)c2ccccc2C(=O)[O-])C=C1I
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@@H](N)Cc2cccc(C#N)c2)CC1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
TIPPS-3-cyano-(L)-phenylalanine (215 g; 0.435 mmol; 93% purity), ethyloxycarbonylpiperazine (68.8 g; 0.435 mmol) and 1-hydroxybenzotriazole. (13.3 g; 0.087 mol) were dissolved in 650 ml of DMF and cooled to 10° C. A solution of dicyclohexylcarbodiimide (98.7 g; 0.478 mol) in 216 ml of DMF was added dropwise over a period of 2 h and the reaction solution was stirred at RT overnight. After evaporating the solvent, the residue was dissolved in 436 ml of MTBE, the precipitate was filtered off, and the organic solution was extracted in each case 2× with 5% KHSO4, 5% NaHCO3 and distilled water. The solvent was evaporated under vacuum, toluene was added and then evaporated in a rotary evaporator and the product was dried under vacuum.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([Cl:23])[CH:14]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:18]1[C:17]2[CH:16]=[C:15]([Cl:23])[CH:14]=[C:13]([Br:12])[C:22]=2[O:21][CH2:20][CH2:19]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Clc1cc(Br)c2c(c1)NCCO2
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCOc2c(Br)cc(Cl)cc21
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Benzyl chloroformate (1.877 g, 0.011 mol) was added dropwise to a solution of 8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine (2.85 g, 0.01 mol) in a 1:1 mixture of ethyl acetate (30 mL) and 10% aqueous sodium hydroxide (30 mL). After 3 hours at ambient temperature, the layers were separated and the organic phase was washed with water (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), dried (K2CO3) and concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with hexane-ethyl acetate; 7:3, V/V) to give 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester as an oil (3.47 g, 98%). A sample was recrystallized from ethanol-water. MS: MH+ 383. M.P. 95.0-97.7° C.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:24])([CH3:23])[C@H:7]1[OH:25].[CH:26]([C:28]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:29]=1[C:30](OC)=[O:31])=O>C(O)CC.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:24][C:8]1([CH3:23])[C@@H:7]([OH:25])[C@H:6]([N:5]2[CH2:26][C:28]3[C:29](=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)[C:30]2=[O:31])[C:11]2[CH:12]=[C:13]([S:16]([C:19]([F:21])([F:22])[F:20])(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[O:9]1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCO
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3ccc([N+](=O)[O-])cc3C2=O)[C@@H]1O
Reaction time: 1.5 h
Yield: 87 %

Procedure:
A solution of 0.164 g of zinc chloride and 0.075 g of sodium cyanoborohydride in 3.3 ml of propanol was added to a solution of 0.326 g of trans-4-amino-3,4-dihydro-2,2-dimethyl-6-trifluoromethylsulfonyl 2H-1-benzopyran-3-ol (prepared from its hydrochloride prepared as described in Preparation 9) and 0.224 g of methyl 2-formyl-5-nitrobenzoate in 3.3 ml of propanol, and the resulting mixture was heated under reflux in an oil bath kept at 140° C. for 1.5 hours. At the end of this time, the reaction mixture was diluted with 150 ml of ethyl acetate, and the resulting solution was washed with 1N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The mixture was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and hexane to give 0.424 g of the title compound, melting at 264°-266° C.
Reaction SMILES: [Mg].BrC(Br)C.C(Cl)(C)C.Br[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1.C(Cl)(Cl)Cl.O.CO.CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Brc1cccnc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(Br)Br
Agent: CC(C)Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Reaction time: 0.25 h

Procedure:
(Apparatus: 1 I three-necked flask with nitrogen balloon) Magnesium (5.7 g) was initially introduced into anhydrous ether (125 ml), 1,1-dibromoethane (0.5 g) and isopropyl chloride (17.3 ml) were added dropwise and the mixture was stirred for 15 min to initiate the magnesium. A solution of 3-bromopyridine (25 g) in anhydrous tetrahydrofuran (400 ml) was added dropwise at 40° C. over the course of 20 min and the mixture was then refluxed for 2 h. A solution of 1-benzylpiperidin-4-one (30 g) in anhydrous tetrahydrofuran (100 ml) was finally added dropwise at 40° C. over the course of 20 min and the mixture was stirred at room temperature overnight. Thin layer chromatography control: 10% methanol in chloroform. The reaction mixture was hydrolysed with water (50 ml) at 0° C. and filtered over Celite. Extraction was carried out with methylene chloride (2×100 ml) and the combined organic phases were washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (Alox neutral) with 5% methanol in chloroform. Yield: 8.2 g (19%)
Reaction SMILES: CO[CH:3]([O:11]C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[OH-].[Na+].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O>[C:15]([NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:11])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(OC)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
1.06 g of 3-aminobenzaldehyde dimethyl acetal was dissolved in a mixture of 5 ml of toluene and 10 ml of water containing 0.8 g of sodium hydroxide, and 5 ml of a toluene solution of 1.3 g of benzoyl chloride was added. The mixture was stirred at room temperature for 2 hours. The organic layer was separated, and evaporated under reduced pressure. The residue was dissolved in a mixture of 10 ml of methanol and 10 ml of 10% hydrochloric acid, and heated at 90° C. for 30 minutes. Water (20 ml) was added to the reaction mixture to allow it to cool. There was obtained 1.16 g (yield 87.3%) of 3-benzoylaminobenzaldehyde as colorless needles having a melting point of 122° to 123° C.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:25][O:26]CC2C=CC=CC=2)[CH2:16][O:17]CC2C=CC=CC=2)=[O:13])[O:5][C@@H:4]([N:35]2[C:45]3[N:44]=[C:42]([NH2:43])[NH:41][C:39](=[O:40])[C:38]=3[N:37]=[CH:36]2)[CH2:3]1>C(OCC)(=O)C.CO.C(O)(=O)C.[Pd]>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][C:12]([O:14][CH:15]([CH2:16][OH:17])[CH2:25][OH:26])=[O:13])[O:5][C@@H:4]([N:35]2[C:45]3[N:44]=[C:42]([NH2:43])[NH:41][C:39](=[O:40])[C:38]=3[N:37]=[CH:36]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](COC(=O)CCC(=O)OC(COCc3ccccc3)COCc3ccccc3)O2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](COC(=O)CCC(=O)OC(CO)CO)O2)c(=O)[nH]1

Procedure:
A solution of 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(1,3-dibenzyloxy-2-propyloxy carbonyl)propanoyl]guanosine (3.2 g, 5.13 mmole) in 50 ml ethyl acetate, 50 ml methanol and 10 ml acetic acid was hydrogenated with palladium black (0.6 g) under 40 psi overnight. The catalyst was filtered and washed with methanol, The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography. Yield: 1.64 g
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17](=[CH:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][CH:4]2[OH:21])[CH:16]=[C:15]([OH:20])[CH2:14][CH2:13]4)[CH3:2].[CH3:22][C:23](CC(O)=O)=[O:24].BrN1C(=O)CCC1=O>CC(C)=O.N1C=CC=CC=1.C([O-])(=O)C.[Na+].O.C(O)(=O)C>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH:18]=[CH:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:23](=[O:24])[CH3:22])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC(=O)CC(=O)O
Reactant: CC[C@]12CC[C@H]3[C@@H](CC=C4C=C(O)CC[C@@H]43)[C@@H]1CCC2O
Agent: CC(=O)[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(C)=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Add dl-13-ethyl-3,17-dihydroxygona-3,5-diene, diacetate (1.0 g) dissolved in acetone (20 cc) to a solution of acetone (86 cc), pyridine (.59 ml), sodium acetate (2.72 cc), water (27.2 cc) and acetic acid (2.72 cc). Chill to 0° and add N-bromosuccinimide (0.5 g). Stir for three hours at a temperature between +5 and -5°. Pour into ice-cold brine (800 cc) and extract with ether. Wash and dry the ether layer and concentrate, deeping the temperature below +15°. Add calcium carbonate (3.0 g) and dimethylformamide (70 cc) and distil off residual ether. Reflux one hour, cool and filter; wash the cake with ether. Pour the filtrate into brine and extract with ether. Recrystallize from ethyl acetate-hexane to obtain dl-13-ethyl-17β-acetoxygona-4,6-dien-3-one (0.475 g), m.p. 163°-177°, λ max. KBr 5.77, 6.0 μ; λ max. EtOH 283 mμ (ε24,370).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][NH:10][C:11]([CH:13]2[CH2:15][CH2:14]2)=[O:12])=[CH:7][CH:6]=1.[CH2:18](Br)[C:19]#[CH:20].C1(C)C=CC=CC=1>CCOCC.C1COCC1>[CH3:3][O:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]([CH2:20][C:19]#[CH:18])[C:11]([CH:13]2[CH2:14][CH2:15]2)=[O:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(CNC(=O)C2CC2)cc1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCN(Cc1ccc(OC)cc1)C(=O)C1CC1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
Sodium hydride (60% in mineral oil, 709 mg, 17.72 mmol) was washed with dry ether (2×20 mL) and then suspended in dry THF (30 mL) and cooled with ice-water. Crude N-(4-methoxybenzyl)cyclopropanecarboxamide from last step in THF (5 mL) was added dropwise at 5° C. to the sodium hydride suspension. The reaction mixture was stirred at 5° C. for 20 min. A solution of propargyl bromide in toluene (80% wt., 2.69 mL, 24.17 mmol) was added dropwise with a syringe. The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water (100 mL) and extracted with DCM (3×100 mL). The organic phases were combined and washed with brine (2×50mL), dried with anhydrous MgSO4, filtered and evaporated to dryness, then purified by silica gel column chromatography, eluting with MeOH/DCM (0-2%) to give the product (2.43 g, 62.0% yield), LRMS ESI (M+H+) 244.
Reaction SMILES: O=[C:2]1[CH2:11][C:10]2[CH:9]=[C:8]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[C:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C([BH3-])#N.[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][N:33]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][C:8]([N:12]4[C:20](=[O:21])[C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[C:13]4=[O:22])=[CH:7][CH:6]=3)[CH2:11]2)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCc2ccc(N3C(=O)c4ccccc4C3=O)cc2C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C2CCc3ccc(N4C(=O)c5ccccc5C4=O)cc3C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a flask charged with 2-(7-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-isoindole-1,3(2H)-dione (0.25 g, 0.86 mmol), N-Boc piperazine (0.24 g, 1.3 mmol), and a stir bar was added titanium isopropoxide (2.5 mL), ethanol (10 mL), and sodium cyanoborohydride (0.27 g, 4.3 mmol). The mixture was allowed to stir at RT for 2 hours. LC showed formation of the desired product at that point. The reaction was diluted with EtOAc (50 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated, and purified by MPLC to afford the desired product. LC-MS (IE, m/z): 462 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:17])[NH:16][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH3:28]>CN(C=O)C.O>[C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:17])[N:16]([CH2:27][CH3:28])[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)NC(=O)OCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)OCCc2ccc(C(=O)OC(C)(C)C)cc21

Procedure:
A mixture of 6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester (1.1 g, 4.18 mmol), potassium carbonate (2.5 g, 18.1 mmol, 4.3 eq.) and iodoethane (1.67 mL, 20.87 mmol, 5 eq.) was stirred in DMF (20 mL) for 16 hours at 60° C. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (sodium sulfate) and concentrated. Silica gel chromatography (0→20% ethyl acetate in hexanes) provided 5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester as pale solid in quantitative yield: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.80 (dd, 1H), 7.28 (d, 1H), 4.48 (t, 2H), 3.91 (q, 2H), 3.00 (t, 2H), 1.59 (s, 9H), 1.23 (t, 3H).