Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:8]([CH2:15][CH2:16][CH2:17][OH:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])=[N:5]1)(=[O:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]([N:4]1[C@:8]([CH2:15][CH2:16][CH:17]=[O:18])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:7][C:6]([C:19]2[CH:24]=[C:23]([Br:25])[CH:22]=[CH:21][C:20]=2[F:26])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2cc(Br)ccc2F)CC1(CCCO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)N1N=C(c2cc(Br)ccc2F)C[C@@]1(CCC=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 180 mg (0.429 mmol) 3-5 in 2.0 mL DCM at RT under N2 was added 218 mg (0.515 mmol) Dess-Martin Periodinane. After stirring for 30 min, the reaction was quenched by slowly adding saturated aqueous Na2SO3 solution followed by saturated aqueous NaHCO3 solution. The mixture stirred for 15 min before it was poured into EtOAc and separated. The organic phase was washed with 1:1 saturated aqueous Na2SO3-saturated aqueous NaHCO3 solution, water, brine, then dried with Na2SO4 and concentrated to yield 3-6 as a white foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])[CH3:2].Br.C(N(CC)CC)C.[C:28]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([O:31][C:28](=[O:30])[CH3:29])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)c1ccc(OC(C)=O)cc1
Reaction time: 3 h

Procedure:
17.3 g (0.05 mol) of L-alanyl-L-phenylalanine ethyl ester·HBr was suspended in 250 ml of dichloromethane, and to this susension were added 5.1 g (0.05 mol) of triethylamine and 9 g (0.05 mol) of p-acetoxybenzoic acid, and then 9.6 g (0.05 mol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide·HCl was added in an ice bath. This mixture was stirred for three hours, and then was washed with a 0.1% aqueous solution of Na2CO3 and with a 0.1 N HCl solution three times and then with distilled water three times, and was dried over anhydrous sodium sulfate. Dichloromethane was removed from the dried mixture under reduced pressure to obtain p-acetoxybenzoyl-L-alanyl-L-phenylalanine ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)([OH:24])=[O:23].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(OB(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(C(=O)O)cc2)CC1

Procedure:
In 1,2-dimethoxyethane (30 ml), 4-(1-tert-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine (3.59 g) was dissolved, followed by the addition of 4-carboxyphenylboric acid (3.60 g), lithium chloride (1.38 g), tetrakistriphenylphosphine palladium (0.62 g) and an aqueous solution of sodium carbonate (2M, 16.3 ml). The resulting mixture was heated under reflux for 2 hours under an argon gas atmosphere. To the reaction mixture, 1N hydrochloric acid was added. The resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (dichloromethane˜dichloromethane:methanol 100:1). The purified product was pulverized and washed in a mixed solvent of hexane and ethyl acetate (hexane:ethyl acetate 5:1), whereby the title compound (462 mg, 14%) was obtained.
Reaction SMILES: [CH3:1][N:2]([C@@H:4]1[C:23]([OH:24])=[C:22]([C:25]([NH2:27])=[O:26])[C:20](=[O:21])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:17](=[C:18]2[OH:29])[C:15](=[O:16])[C:14]2[C:13]([OH:30])=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH3:3].[I:31]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[CH3:3][N:2]([C@@H:4]1[C:23](=[O:24])[C:22]([C:25]([NH2:27])=[O:26])=[C:20]([OH:21])[C@:19]2([OH:28])[C@H:5]1[CH2:6][C@H:7]1[C:17]([C:18]2=[O:29])=[C:15]([OH:16])[C:14]2[C:9](=[C:10]([I:31])[CH:11]=[CH:12][C:13]=2[OH:30])[CH2:8]1)[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4C[C@H]3C[C@@H]12
Agent: O=S(=O)(O)O
Product: CN(C)[C@@H]1C(=O)C(C(N)=O)=C(O)[C@@]2(O)C(=O)C3=C(O)c4c(O)ccc(I)c4C[C@H]3C[C@@H]12
Temperature: 0 °C

Procedure:
Five grams of sancycline was dissolved in 85 mL of concentrated sulfuric acid that was cooled to 0° C. (on ice). N-iodosuccinimide (NIS) was added to the reaction in 300 mg portions every 15 minutes and reacted for 5 hours. The reaction is removed from the ice bath. The mixture, analyzed by HPLC or TLC, show the product of D-ring iodotetracyclines. After the reaction was complete, the sulfuric acid was dripped slowly 1 L of ice water and extracted 7 times with 300 mL of n-butanol. The solvent was removed in vacuo to produce a mixture of three products. The 7-iodo regioisomer, 9-regioisomer and 7,9-diiodosancycline derivative of sancycline were purified by preparative HPLC chromatography or by methods known in the art.
Reaction SMILES: C[NH:2][C:3]([CH3:21])=[C:4]([C:15](=O)[C:16]([F:19])([F:18])[F:17])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].O.[NH2:23]N.O.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C.CCOC(C)=O>[CH3:21][C:3]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:15]([C:16]([F:19])([F:18])[F:17])[NH:23][N:2]=1
Reactant: NN
Reactant: CNC(C)=C(C(=O)OCc1ccccc1)C(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1n[nH]c(C(F)(F)F)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of benzyl 3-(methylamino)-2-(trifluoroacetyl)but-2-enoate (90 g, 300 mmol) in a mixture of THF (900 mL) and acetic acid (100 mL) was added hydrazine monohydrate (14.6 mL, 300 mmol) over a 5 min period. The reaction mixture was heated to reflux for 3 hours, allowed to cool to room temperature and the solvents were evaporated in vacuo to afford a bright yellow mass. The mass was dissolved in EtOAc (1 L) and water (1 L) with gentle heating, allowed to cool to room temperature and the aqueous layer was neutralized to pH 7-8 with NaHCO3. This mixture was transferred to a 3-L separating funnel, the layers were mixed vigorously, separated and the organic layer was washed with water (3×500 mL) dried (MgSO4), filtered and evaporated in vacuo to give benzyl 3-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as an off-white solid in 89% yield 74 g that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15]C(C3CC3)=O)[CH:10]=2)[C:5](=[O:21])[N:4]2[C:22]([C:27]3C=[CH:31][CH:30]=[C:29](F)[CH:28]=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.ClC1C=C(N(CC2C=CC(OC)=CC=2)C2C=CN=CN=2)C(=O)[N:37]2C3(CCCCC3)N(CC3C=CC(OC)=CC=3)C(=O)[C:36]=12.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C(O)(C)(C)C.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]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:37]=[CH:36][C:10]=23)[C:5](=[O:21])[N:4]2[C:22]3([NH:23][C:24](=[O:25])[C:3]=12)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3
Reactant: COc1ccc(CN(c2ccncn2)c2cc(Cl)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: O=C1NC2(CCCCC2)n2c1c(Cl)cc(Nc1ncnc3[nH]ncc13)c2=O
Temperature: 90 °C

Procedure:
To a suspension of 6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (1, 0.5 g, 1.51 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (2, 0.2 g, 1.51 mmol) in tert-butanol (20 mL) in a vial, potassium phosphate (0.96 g, 4.54 mmol) was added and the reaction mixture was degassed with argon for 15 min. To this mixture XantPhos (4 mg, 0.08 mmol) and Pd2(dba)3 (7 mg, 0.08 mmol) was added and the reaction mixture was further degassed with argon for 5 min. The reaction mixture was heated at 90° C. for 18 h. TLC showed consumption of starting material, the reaction mixture was filtered over celite bed and washed with dichloromethane followed by concentration of the filtrate. The crude was stirred with methanol (10 mL) and filtered. The resulting solid was further washed with diethyl ether (20 mL) and dried under vacuum to afford 8-chloro-6-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione (Cpd. No. 145). Yield: 0.037 g, 6%; MS (ESI) m/z 386.36 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 9.55 (s, 1H), 8.91 (s, 1H), 8.61 (s, 2H), 2.97 (m, 2H), 1.76-1.56 (m, 7H), 1.23 (m, 1H).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[F:17][C:18]([F:22])([F:21])[CH2:19][OH:20]>O.Cl>[F:17][C:18]([F:22])([F:21])[CH2:19][O:20][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: OCC(F)(F)F
Reactant: O=C(O)c1cccnc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)c1cccnc1OCC(F)(F)F
Yield: 32 %

Procedure:
2-Fluoropyridine-3-carboxylic acid (200 mg, 1.42 mmol) was dissolved in 2,2,2-trifluoroethanol (2 mL) and potassium tert-butoxide (477 mg, 4.25 mmol) was added. The mixture was then heated to 90 C for 4 h. The mixture was diluted with water (4 mL), 2M HCl was added to bring the solution to pH 4 and the mixture was extracted with DCM (3×4 mL). 2M HCl was added to the aqueous layer to bring the solution to pH 3 and the mixture was extracted with DCM (4×5 mL). The combined organic extractions were dried over sodium sulfate and evaporated under vacuum to afford the title compound (100 mg, 32%). Method C HPLC-MS: MH+ requires m/z=222. Found: m/z=222, Rt=1.17 min (100%).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:9][OH:10]>F[B-](F)(F)F.C[N+](C)(C)C>[C:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH3:9])(=[O:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)N1CCCC1
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCN1C(C)=O

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 19.6 g of N-acetylpyrrolidine and 55.6 of methanol in the presence of 0.28 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.0 Faraday per mol of N-acetylpyrrolidine the current is switched off. The calculated mean cell voltage is 32.7 volts. Work-up of the electrolysis solution gives 19.9 g of 1-acetyl-2-methoxypyrrolidine (boiling point 53° C./0.1 mbar; nD25 =1.4674), which corresponds to a product yield of 80.0% and a current efficiency of 80.0%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2].C([NH:22][CH2:23][CH2:24]O)(OC(C)(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(Cl)Cl.C(O)(C(F)(F)F)=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH2:24][CH2:23][NH2:22])[C:7]([O:9][CH3:10])=[O:8])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(OCCN)c([N+](=O)[O-])c1
Yield: 38.6 %

Procedure:
To a stirred solution of methyl 3-nitro-4-hydroxybenzoate (1.98 g, 10.04 mmol), N-Boc ethanolamine (1.63 g, 10.11 mmol) and PPh3 (3.43 g, 13.08 mmol) in THF (40 mL) was added DIAD (2.57 mL, 13.05 mmol), and the reaction mixture was then heated under reflux overnight. The resulting mixture was evaporated to give a gum. The residual crude gum was dissolved in CH2Cl2 (30 mL) and TFA (30 mL), and the mixture was stirred for 1 hr at room temp. The mixture was concentrated in vacuo and made basic with sat. NaHCO3. The mixture was extracted with CHCl3, washed with brine, and dried over Na2SO4. The solvent was evaporated in vacuo to give the oily residue, which was purified by column chromatography on silica -gel with CHCl3 then CHCl3-MeOH (20:1, v/v) as eluent to give 930 mg (27% for 2 steps ) methyl 3-nitro4-(2-aminoethoxy)benzoate as gum. 1H-NMR (CDCl3) δ 3.16–3.19 (m, 1 H), 3.53–3.57 (m, 1 H), 3.90 and 3.94 (s, 3 H), 3.95–3.98 (m, 1 H), 4.21–4.24 (m, 1 H), 6.89–6.91 and 7.11–7.13 (m, 1 H), 8.03–8.19 and 8.21 (m, 1 H), 8.52 and 8.86 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6]([C:8]#[C:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:27][CH:26]=2)=[O:23])=[O:11])[CH:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:38]2[CH:42]=[N:41][N:40]=[N:39]2)=[C:6]([C:8]#[C:9][C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C@H:13]2[C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:36][CH:37]=2)=[O:23])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)C#Cc2cc(Cl)ccc2-n2cnnn2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(NC(=O)[C@@H]2c3ccccc3CCN2C(=O)C#Cc2cc(Cl)ccc2-n2cnnn2)cc1
Reaction time: 24 h

Procedure:
(S)-tert-Butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)propioloyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoate: Combined 48C (0.055 g, 0.221 mmol), 3B (0.078 g, 0.221 mmol), BOP (0.098 g, 0.221 mmol), and DIEA (0.039 mL, 0.221 mmol) in DMF (1 mL). After 24 h, the reaction was partitioned with H2O (10 mL) and brine (10 mL) and EtOAc (60 mL). The organic layer was washed with brine (10 mL) and dried (MgSO4). MS (ESI) m/z: 582.9 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Si:11]([O:18][CH2:19][C:20]([C:23]1[CH:24]=[C:25]([C:30]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([NH2:37])[N:31]=2)[C:26](F)=[N:27][CH:28]=1)([CH3:22])[CH3:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].[F:38][C:39]1[CH:40]=[C:41]([NH2:47])[CH:42]=[N:43][C:44]=1[O:45][CH3:46]>C1COCC1>[Si:11]([O:18][CH2:19][C:20]([C:23]1[CH:24]=[C:25]([C:30]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]([NH2:37])[N:31]=2)[C:26]([NH:47][C:41]2[CH:42]=[N:43][C:44]([O:45][CH3:46])=[C:39]([F:38])[CH:40]=2)=[N:27][CH:28]=1)([CH3:21])[CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: Cc1nc(N)nc(-c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cnc2F)n1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Sodium bis(trimethylsilyl)amide (1.0M in THF) (Aldrich, St. Louis, Mo.; 0.447 mL, 0.447 mmol) was added to an orange-brown solution of 4-(5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (73.0 mg, 0.186 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, North Brunswick, N.J.; 31.8 mg, 0.224 mmol) in THF (2.0 mL) at 0° C., and the resulting brown solution was stirred at 0° C. for 1 h. Excess sodium bis(trimethylsilyl)amide was carefully quenched with saturated aqueous NH4Cl (5 mL), and the resulting mixture was partitioned between CH2Cl2 (50 mL) and half-saturated aqueous NH4Cl (30 mL). The aqueous layer was extracted with CH2Cl2 (30 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0 to 70% EtOAc/hexanes) furnished 4-(5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (88.8 mg, 0.173 mmol, 93% yield) as a yellow-orange solid. m/z (ESI, +ve) 514.0 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C:48](=[O:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([O:56][Si](C(C)C)(C(C)C)C(C)C)[CH2:5][C:4]1=[O:67])[CH3:2].C1C=CN=CC=1.F>O1CCCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([F:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][C:48](=[O:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:67])[CH3:2]
Reactant: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O[Si](C(C)C)(C(C)C)C(C)C)CC1=O)C(C)CC2OC
Agent: *CC(*)C
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCC1C=C(C)C(F)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a stirred solution of 17-ethyl-20-fluoro-1-hydroxy-12-[2'-(3"-methoxy-4"-oxocyclohexyl)-1'-methylvinyl]-14-triisopropylsilyloxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,18-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10, 16-tetraone from Example 23 (870 mg) in tetrahydrofuran (20 ml) contained in a polypropylene vial is added 4 ml of an HF-pyridine solution in tetrahydrofuran and the mixture was stirred at room temperature. The reaction mixture is quenched with sat'd aqueous sodium bicarbonate. The organic layer is separated and the aqueous layer is extracted with ethyl acetate three times. Combined organic layers are washed (sat'd NaHCO3, sat'd NaCl), dried (anhydrous Na2SO4), and filtered. Removal of solvent followed by purification (silica gel column chromatography, gives the title compound.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([Cl:32])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:5][C:4]1[C:25]([Cl:32])=[CH:26][C:27]([O:30][CH3:31])=[C:28]([Cl:29])[C:3]=1[Cl:2])[CH3:34]
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1Cl
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(Cl)cc(OC)c(Cl)c1Cl

Procedure:
By the procedure of Example 1, 2,3,6-trichloro-4-methoxy-benzyltriphenyl-phosphonium chloride is reacted with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(2,3,6-trichloro-4-methoxy-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester of melting point 126°-128° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4](I)[CH:3]=1.[C-:10]#[N:11].[Na+]>N1C=CC=CC=1>[C:10]([C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH2:6])#[N:11]
Reactant: [C-]#N
Reactant: Nc1ccc(F)cc1I
Agent: [Na+]
Solvent: c1ccncc1
Product: N#Cc1cc(F)ccc1N

Procedure:
Fifteen grams of cuprous cyanide and 14 g. of dry pyridine are heated to a homogeneous melt. After adding 25.0 g. of 4-fluoro-2-iodoaniline, the mixture is heated at about 160°-170° C. for two hours. To the cooled mixture, concentrated sodium cyanide solution is added. The solid material is filtered off and extracted with benzene. The benzene extracts are concentrated and fractionally distilled to give 2-cyano-4-fluoroaniline.
Reaction SMILES: [C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([OH:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[C:1]([O:9][CH:10]([O:14][C:15]([NH:17][CH2:18][C:19]1([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])[CH:11]([CH3:12])[CH3:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(OC(=O)NCC1(CC(=O)O)CCCCC1)OC(=O)c1ccccc1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)C(C)C)CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 1-{[(α-benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid (84) (150 mg, 0.38 mmol), benzene (18 mL), and methanol (2 mL) was cooled to 0° C. Trimethylsilyldiazomethane was added slowly at 0° C. until the yellow color persisted. The mixture was stirred at 0° C. for 30 min until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, chromatography of the residue on silica gel, eluting with 5% ethyl acetate/hexane gave 98 mg (64%) of the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.02 (d, J=6.4 Hz, 3H), 1.03 (d, J=6.4 Hz, 3H), 1.32–1.52 (m, 10H), 2.14 (m, 1H), 2.27 (s, 2H), 3.17 (m, 2H), 3.62 (s, 3H), 5.40 (t, 1H), 6.81 (d, J=4.8 Hz, 1H), 7.40 (m, 2H), 7.54 (m, 1H), 8.12 (m, 2H). MS (ESI) m/z 406.29 (M+H+).
Reaction SMILES: [Na].[CH:2](OCC)=O.N1C=CC=C(COCC(OCC)=O)C=1.C(C(OCC1C=NC=CC=1)C(OCC)=O)=O.NC(N)=S.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][O:48][C:49]2[C:50](=[O:56])[NH:51][C:52](=[S:55])[NH:53][CH:54]=2)[CH:42]=1.N1C=CC(=O)NC1=O.[OH-].[Na+].CI>CCOCC.O.C(O)C>[CH3:2][S:55][C:52]1[NH:51][C:50](=[O:56])[C:49]([O:48][CH2:47][C:43]2[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=2)=[CH:54][N:53]=1
Reactant: CCOC=O
Reactant: O=c1[nH]c(=S)[nH]cc1OCc1cccnc1
Agent: CCOC(=O)C(C=O)OCc1cccnc1
Agent: CCOC(=O)COCc1cccnc1
Agent: NC(N)=S
Solvent: CI
Solvent: O
Solvent: CCO
Product: CSc1ncc(OCc2cccnc2)c(=O)[nH]1

Procedure:
Following the above procedure, 3.03 g. of sodium were suspended in anhydrous ether in a nitrogen atmosphere. 5.93 g. of ethyl formate plus 14.1 g. of ethyl 3-pyridylmethoxyacetate were added. The product of the reaction, ethyl formyl-(3-pyridylmethoxy)acetate as the sodium salt, was suspended in 175 ml. of ethanol and 5.8 g. of thiourea were added. The product of this reaction, 5-(3-pyridylmethoxy)-2-thiouracil, melted at 243°-245° C.; weight=10.4 g. 9.9 g. of the uracil were slurried in 80 ml. of ethanol. A solution containing 1.78 g. of sodium hydroxide and 38 ml. of water was added followed by 4.86 g. of methyl iodide. 1.46 g. of 2-methylthio-5-(3-pyridyl)methoxy-4-pyrimidone were obtained melting at 186°-187° C.