Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].[Cs+].[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[CH:6]=[O:7].C[Si](C)(C)[C:15]([F:18])([F:17])[F:16].Cl>C1COCC1.O>[F:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:5]=1[CH:6]([OH:7])[C:15]([F:18])([F:17])[F:16]
Reactant: O=Cc1c(F)cccc1F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1c(F)cccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.1 %

Procedure:
Caesium fluoride (32 mg, 2.1 mmol) was added to a mixture of 2,6-difluoro-benzaldehyde (2 ml, 18.2 mmol) and trimethyl(trifluoromethyl)silane (2 ml, 19.6 mmol) in THF (30 ml) at room temperature. The suspension was stirred at room temperature for 6 hours and stored at room temperature 18 hours. A mixture of concentrated hydrochloric acid (3 ml) in water (7 ml) was added and the solution was stirred at room temperature for 4 hours. The mixture was concentrated to give the product (3.4 g, 87% yield) which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:14])([CH3:13])[C:11]#[N:12].N.CO>[Rh]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12]
Reactant: CC(C)(C#N)c1cc2ccccc2[nH]1
Agent: [Rh]
Agent: N
Solvent: CO
Product: CC(C)(CN)c1cc2ccccc2[nH]1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
A mixture of 2-(indol-2-yl)-2-methylpropiononitrile (300 mg) and 5% rhodium on alumina powder (500 mg) in 10N-ammonia-methanol was hydrogenated at 50-60 psi for 8 hours. After filtration of the catalyst, the filtrate was evaporated in vacuo to give 2-(indol-2-yl)-2-methylpropylamine (306 mg) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6]P(=O)([O-])[O-])=[CH:4][CH:3]=1.C1OCCOCCOCCOCCOC1.[H-].[Na+].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>C1COCC1.O>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40](=[CH:6][C:5]2[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=P([O-])([O-])Cc1ccc(F)cc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(F)cc2)CC1
Yield: 76.5 %

Procedure:
4-fluorobenzyl bromide (100 g) and triethyl phosphite (120 ml) were mixed, and the mixture was stirred at 150° C., for 22 hours. The obtained reaction mixture was distilled under reduced pressure (bp 115-120° C./1.5 mmHg) to give diethyl 4-fluorobenzylphosphonate (125 g). To a solution of 4-fluorobenzylphosphonate (60.8 g), 15-Crown-5 (4 ml) in THF (400 ml) was added 60% sodium hydride in mineral oil (9.75 g) under ice cooling with stirring, and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of 1-tert-butoxycarbonyl-4-piperidone (42.0 g) in THF (150 ml) under ice cooling, and the mixture was stirred at room temperature for 22 hours. After the addition of water under ice cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate, saturated aqueous solution of sodium chloride, successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 650 g, hexane/ethyl acetate=30/1 to 10/1), and the desired fraction was concentrated under reduced pressure to give 1-tert-butoxycarbonyl-4-(4-fluorobenzylidene)piperidine (47.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH3:12]>CO.[Ni]>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([F:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: CO
Product: Cc1cc(F)c(N)cc1Br
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 1-bromo-4-fluoro-2-methyl-5-nitrobenzene (20 g, 85.8 mmol) in methanol (300 mL) was added Raney Ni (20%/w, ˜2.0 g, suspension in water, washed with acetone for several times), then the resulting mixture was hydrogenated under hydrogen atmosphere for 2 h. The catalyst was filtered, concentrated, and tire residue was recrystallized (petroleum ether) to afford 5-bromo-2-fluoro-4-methylphenylamine (10 g, 57.5% yield). 1HNMR (400 MHz, DMSO-d6): δ 7.12 (d, J=10.2 Hz, 1 H), 6.78 (d, J=10.9 Hz, 1 H), 4.85 (s, 2 H), 2.29 (s, 3 H), 1.26 (s, 12 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH2:10][N:9]([CH2:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21][CH3:22])=[O:20])[C:8]=2[CH:13]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cccc(CN2CCOc3ccc([N+](=O)[O-])cc32)c1
Yield: 85 %

Procedure:
A mixture of 6-nitro-2,3-dihydrobenz-1,4-oxazine (0.45 g.), methyl 3-bromomethylbenzoate* (Y) (0.58 g.), potassium carbonate (0.35 g.), and sodium iodide (0.38 g.) in dry 2-butanone (25 ml.) was stirred and heated under reflux for 48 hours. The cooled reaction mixture was filtered, the filter cake washed with 2-butanone, and the combined filtrate evaporated. The product was purified by flash chromatography on silica gel, eluting with 5:95 v/v ethyl acetate: toluene to give methyl 3-(6-nitro-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)benzoate (0.7 g., 85%) as a yellow oil; partial NMR (80 MHz, CDCl3): 3.5(m,2H, N.CH2.CH2O); 3.9(s,3H, OMe); 4.3(m,2H, N.CH2.CH2O); 4.6 (s, 2H, NCH2Ar).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.[CH3:28][N:29]1[C:33]([CH2:34][CH2:35]O)=[CH:32][CH:31]=[N:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:28][N:29]1[C:33]([CH2:34][CH2:35][O:27][C:24]2[CH:23]=[CH:22][C:21]([CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)=[CH:26][CH:25]=2)=[CH:32][CH:31]=[N:30]1
Reactant: Oc1ccc(C2CCNCC2)cc1
Reactant: Cn1nccc1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cn1nccc1CCOc1ccc(C2CCNCC2)cc1
Temperature: 22 °C
Reaction time: 72 h
Yield: 99.3 %

Procedure:
DIAD (64.8 μl, 0.33 mmol) was added to 4-(piperidin-4-yl)phenol (CAS 263139-27-1, 53 mg, 0.30 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (obtained as described in PCT Int. Appl. WO 2007017222, Intermediate 1) (37.7 mg, 0.30 mmol) and triphenylphosphine (86 mg, 0.33 mmol) in DCM (3 mL) at 20° C. under nitrogen. The resulting mixture was stirred at 22° C. for 3 days. The reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M ammonia in methanol and pure fractions were evaporated to dryness to afford 4-[4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl]piperidine (85 mg, 96%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[N:14]([CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:17]=3)O)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:13]3[N:14]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:17]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(NCc3ccc(F)cc3)cc2Cc2c[nH]c3ncc(Cl)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a quartz vial, (5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[5-(4-fluoro-benzylamino)-2-(4-methoxy-benzyl)-2H-pyrazol-3-yl]-methanol (148, 0.328 g, 0.506 mmol) was combined with 20 mL of dichloromethane, triethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroacetic acid (0.2 mL, 2.0 mmol). The reaction was stirred overnight at room temperature, then concentrated under vacuum and ethyl acetate was added. This was washed with 1 M aqueous potassium carbonate and brine, dried with sodium sulfate, and purified by silica gel column chromatography, eluting with 2-20% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum, and the solid further washed with ethyl acetate and hexane to provide the desired compound. 1H NMR was consistent with compound structure.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14]([C@@H:16]1[CH2:20][C:19](=[O:21])[CH2:18][C@H:17]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:15])C1C=CC=CC=1.[OH2:29].[OH-].[Li+].OO>O1CCCC1>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C@@H:17]2[CH2:18][C:19](=[O:21])[CH2:20][C@H:16]2[C:14]([OH:15])=[O:29])=[CH:23][CH:24]=1
Reactant: O=C1C[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Reactant: O
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with a magnetic stir bar was charged with a solution of 1.002 g (2.52 mmol) of the product of Step C dissolved in 41 mL of tetrahydrofuran followed by the addition of 9 mL of water. The reaction mixture was stirred and cooled to 0° C. with an external ice-water bath and a fine suspension was observed. Lithium hydroxide (0.120 g, 5.02 mmol) was added followed by 1.71 mL (15.1 mmol) of 30% aqueous hydrogen peroxide. The reaction mixture was stired for 1 h at room temperature during which time it developed a yellow color. The reaction mixture was then quenched by addition of excess saturated aqueous sodium sulfite and the tetrahydrofuran was removed in vacuo. The residue was extracted three times with methylene chloride to remove the oxazolidinone, then the aqueous layer was adjusted to pH=1–2 with 1 N hydrochloric acid. The aqueous layer was then extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo. The residual amorphous yellow solid (0.412 g) was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16](Br)[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1.[CH3:23][N:24](C)C=O.C1C=CC=CC=1.[C-]#N.[Na+]>O>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[C:16]([C:23]#[N:24])[CH:17]=[CH:18][C:13]=3[CH:12]=[CH:11][N:10]3[CH:20]=[CH:21][CH:22]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3cc(Br)ccc3C=Cn3cccc32)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCC(=C2c3cc(C#N)ccc3C=Cn3cccc32)CC1
Reaction time: 1 h

Procedure:
1-Methyl-4-[9-bromo-11H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine (6.3 g., 0.017 mole) and cuprous cyanide (3.2 g., 0.035 mole) in 25 ml. of dry dimethylformamide are refluxed under nitrogen for five hours. The mixture is cooled to an internal temperature of 50° and treated with 60 ml. each of benzene and aqueous saturated sodium cyanide solution. After stirring one hour the contents are transferred to a separatory funnel with the aid of additional benzene and water. The aqueous phase is extracted two times with benzene, once with ether and the combined benzene-ether extracts are washed successively with dilute sodium cyanide, water, dilute ammonium hydroxide, and water. Upon drying over sodium sulfate the solvents are evaporated in vacuo to give 1-methyl-4-[9-cyano-11H-pyrrolo[2,1-b] [3]benzazepin-11-ylidene]piperidine as an oil (5.0 g., 94%). Trituration with acetonitrile gives a solid (3.6 g., m.p. 156°-159° C.). An analytical sample is obtained after one recrystallization from acetonitrile, m.p. 158°-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)=[CH:35][CH:34]=1.[OH-].[K+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2[CH:45]=[CH:44][S:43][CH:42]=2)=[CH:35][CH:34]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccsc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccsc4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.52 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(thiophen-3-yl-ethynyl)-benzyl]-benzene in 9 mL methanol is added 0.85 mL of 4 M potassium hydroxide solution. The solution is stirred at ambient temperature for one hour and then neutralised with 1 M hydrochloric acid. After the methanol is evaporated the residue is combined with brine and the resultant mixture is extracted with ethyl acetate. The organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→5:1).
Reaction SMILES: C1N=[CH:4][N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.C(N(CC)CC)C.[F:20][C:21]1[CH:27]=[C:26]([I:28])[CH:25]=CC=1N.CN>CN(C)C=O.CO.O.C1(C)C=CC=CC=1>[F:20][C:21]1[CH:27]=[C:26]([I:28])[CH:25]=[CH:10][C:9]=1[NH:8][C:6]([NH:3][CH3:4])=[O:7]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(I)cc1F
Yield: 94.7 %

Procedure:
Under a nitrogen atmosphere, to N,N-carbonyldiimidazole (61.4 g) were added N,N-dimethylformamide (300 ml) and triethylamine (52.8 ml) and a solution of 2-fluoro-4-iodoaniline 47 (74.8 g) in N,N-dimethylformamide (75 ml) was added dropwise with stirring under ice-cooling. After the completion of the dropwise addition, the mixture was stirred at room temperature for 5 hrs. The reaction mixture was ice-cooled, and a solution (60 ml) of 40% methylamine in methanol was added dropwise. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 1125 ml] under stirring. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g, yield 94.8%) as colorless crystals.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[Li].CCOC(C)=O>C1COCC1>[C:9]([O:8][C:7](=[O:13])[NH:6][C@H:4]1[CH2:5][C@@H:2]([OH:1])[CH2:3]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3-oxocyclobutyl)carbamate (100 g, 54 mmol) in THF (2000 mL) at −72° C. was added dropwise a solution of lithium trisec-butylhidridoborate (648 mL, 1 M) in THF over 1.5 hrs. The resulting solution was allowed to warm up to rt and stirred for another 1 hr. TLC (petroleum ether: EtOAc=2:1) showed that the starting material was consumed completely. The reaction was quenched with NH4Cl aqueous. Water (1000 mL) and EtOAc (2000 mL) were added to the mixture. The organic layer was separated, dried over MgSO4 and concentrated to give crude material, which was purified by column chromatography with petroleum ether: EtOAc from 10:1 to 1:2 to afford the title compound (62 g, 61% yield) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:24]O>>[CH3:24][O:2][C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])[C:5]=1[OH:18])=[O:3]
Reactant: CC(C)(C)c1cc(C(=O)O)c(O)c(S(C)(=O)=O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(C(C)(C)C)cc(S(C)(=O)=O)c1O

Procedure:
1.0 g (0.003 mol) of 2-carboxy-4-(1,1-dimethylethyl)-6-methylsulfonylphenol prepared in Example 3 is dissolved in 6 ml of methanol, and heated under reflux with 0.1 ml of concentrated sulfuric acid for 2 days. The mixture is poured onto ice-water, and this is extracted with ethyl acetate, the solvent is removed in vacuo and the residue is subjected to chromatography on silica gel using ethyl acetate/toluene 4:1 as the eluting agent.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=[N:9][C:10]=1[Cl:11].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:11][C:10]1[N:9]=[CH:8][N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:17])([CH3:18])[CH3:19])[C:6]=1[CH2:5][CH2:4][CH:3]=[O:2]
Reactant: COC(=O)CCc1c(Cl)ncn1COCC[Si](C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1CCC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.20 g of 3-[5-chloro-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol4-yl]-propionic acid methyl ester in 10 mL of toluene cooled to −75° C. under nitrogen was added 0.5 mL of 1.5 M diisobutylaluminum hydride. After 1 h at −75° C., the reaction was quenched with 0.2 mL of methanol, allowed to warm to room temperature over 30 min and partitioned between 1N sodium carbonate and ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure. The crude 3-[5-chloro-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-propionaldehyde (0.2 g) was essentially homogeneous by TLC, eluting with ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OC([N:24]([C:32]1[S:41][CH2:40][C@H:39]2[C@:34]([C:51]3[CH:56]=[C:55](Br)[CH:54]=[CH:53][C:52]=3[F:58])([CH2:35][O:36][C@@H:37]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:38]2)[N:33]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>CN(C=O)C.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>[F:58][C:52]1[CH:53]=[CH:54][C:55]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:56][C:51]=1[C@@:34]12[N:33]=[C:32]([NH2:24])[S:41][CH2:40][C@@H:39]1[CH2:38][C@H:37]([CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[O:36][CH2:35]2
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@@]2(c3cc(Br)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Reactant: OB(O)c1cccnc1F
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC1=N[C@@]2(c3cc(-c4cccnc4F)ccc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1
Temperature: 85 °C
Reaction time: 7 h
Yield: 33.5 %

Procedure:
2-Fluoropyridine-3-boronic acid (44.0 mg), tetrakis(triphenylphosphine)palladium (18.0 mg) and a 1 N sodium carbonate solution (312 μl) were added to a solution of N,N-di-(tert-butyloxycarbonyl)-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-benzyloxymethyl-4,4a,5,6,8,8a-hexahydro-7-oxa-3-thia-1-azanaphthalen-2-yl]amine (95 mg) in DMF (6.79 ml). After replacement with nitrogen, the mixture was stirred at 85° C. for seven hours. After cooling to room temperature, the mixture was diluted with water. The aqueous layer was extracted with ethyl acetate, and the organic layer was washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in dichloromethane (4.0 ml). TFA (1.0 ml) was added and the mixture was stirred at room temperature for three hours. Ice was added to the reaction mixture, followed by neutralization with a sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (23.0 mg).
Reaction SMILES: [CH3:1][C:2]1([NH:7][CH2:8][C@@H:9]([C:11]2[CH:12]=[CH:13][C:14]3[N:15](N=N[N:19]=3)[CH:16]=2)[OH:10])[CH2:6][CH2:5][CH2:4][CH2:3]1.[ClH:20].[Cl:21][Sn]Cl>CO>[ClH:21].[ClH:20].[NH2:19][C:14]1[N:15]=[CH:16][C:11]([CH:9]([CH2:8][NH:7][C:2]2([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]2)[OH:10])=[CH:12][CH:13]=1
Reactant: Cl[Sn]Cl
Reactant: CC1(NC[C@H](O)c2ccc3nnnn3c2)CCCC1
Agent: Cl
Solvent: CO
Product: CC1(NCC(O)c2ccc(N)nc2)CCCC1
Reaction time: 16 h

Procedure:
To a solution of 349 mg of (R)-α-[[(1-methyl cyclopentyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol and 0.11 ml of 12 N HCl in 28 ml of methanol, 609 mg of SnCl2 108 2H2O was added and the resulting mixture heated at reflux with stirring for 16 hours. The reaction mixture was concentrated to dryness and the residue partitioned between 25 ml of 80:20 methylene chloride:methanol and 5 ml of 2.5 N NaOH solution. The layers were vigorously stirred and then separated. The aqueous layer was repeatedly extracted with methylene chloride/methanol. The combined extracts were dried with anhydrous magnesium sulfate and concentrated to give 473 mg of crude product. Purification was affected on silica gel prep Tlc plates (80:20:1 methylene chloride: methanol:NH4OH) to give 153 mg of product. Treatment with ethanolic HCl solution followed by precipitation with ether afforded the hydrochloride salt, 140 mq. Analysis: Calc'd. for C13H21N3O·2HCl:
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C(O)(=O)C>O>[OH:17][C:12]1[CH:13]=[C:14]([CH3:16])[N:4]=[C:3]([S:2][CH3:1])[N:5]=1
Reactant: CSC(=N)N
Reactant: CCOC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.1 %

Procedure:
S-Methylisothiourea (22.26 g, 160 mmol) was added to a solution of sodium carbonate (16.9 g, 160 mmol) in water (50 mL) and stirred at room temperature until complete dissolution of the S-methylisothiourea. Ethyl acetoacetate (10.41 g, 80 mmol) was added to the mixture in one portion. After stirring for 60 hours at room temperature, the reaction was neutralized with acetic acid precipitating a white solid. The solid was collected, washed with water, and dried in vacuo to give 4-hydroxy-6-methyl-2-(methylthio)pyrimidine (9.38 g, 75%), m.p. 218-221° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH2:13]([N:15](CC)[CH2:16]C)C.CNC.O1CCCC1>C(#N)C>[CH3:13][N:15]([CH3:16])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A pressure tube was charged with 1-(2-bromoethyl)-4-nitrobenzene (1 g, 4.35 mmol) in acetonitrile (5 mL). Triethylamine (2.4 mL) and dimethylamine, 2M in tetrahydrofuran (0.784 g, 17.39 mmol) were added, and the sealed tube was stirred at ambient temperature for 2 days. The reaction mixture was partitioned between dilute NaHCO3 solution and ethyl acetate, then extracted another two times with ethyl acetate. The product was then extracted into 2N HCl (2×25 mL). Following neutralization with 2N NaOH, the aqueous mixture was extracted with ethyl acetate (3×). The extracts were dried (Na2SO4), filtered and concentrated to give the title compound. MS (ESI(+)) m/e 194.9 (M+H)+.