Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C[O:7][P:8]([O:17]C)([C:10]([S:12]([O:15]C)(=[O:14])=[O:13])=[CH2:11])=[O:9].Br[Si](C)(C)C.O>C(Cl)(Cl)Cl>[N:1]1([CH2:11][CH:10]([P:8]([OH:17])([OH:9])=[O:7])[S:12]([OH:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: C=C(P(=O)(OC)OC)S(=O)(=O)OC
Agent: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=P(O)(O)C(Cn1ccnc1)S(=O)(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 0.68 g (0.01 mole) of imidazole and 2.30 g (0.01 mole) of methyl 1-dimethoxyphosphinylethenesulfonate (U.S. Pat. No. 5,011,938 issued to Barnett et al. on Apr. 30, 1991) in 20 ml of chloroform is stirred at 20°-50° for one day. The reaction is cooled to room temperature, and 10.7 g (0.07 mole) of bromotrimethylsilane is added. The mixture is stirred at 20°-30° for 2-3 days, and to it is then added 20 ml water. The mixture is stirred for about 30 minutes, and the layers are separated. The water layer is extracted several times with CHCl3 (extracts are discarded) and is evaporated to dryness under vacuum. The residue is triturated with acetone to give a solid, which is collected by filtration and recrystallized from water/acetone to afford 2-(1-imidazolyl)-1-phosphonoethanesulfonic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[O:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:22])[C:12](=[CH:18]OCC)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]>>[CH2:8]([O:10][C:11](=[O:22])[C:12](=[CH:18][NH:7][C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]
Reactant: Cc1cc(N)on1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc(C)no1)C(=O)OCC
Reaction time: 0.75 h

Procedure:
112.5 g. of 3-Methyl-5-aminoisoxazole (1.14 mol.) and 248 g. of ethoxymethylenemalonic acid diethyl ester (1.14 mol.) are heated with stirring for 45 minutes at 130°. After this period, ethanol is removed under reduced pressure. The residue solidifies on cooling and is recrystallized from ethanol, m.p. 134°-136°, yield 245 g. (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].[C:12](Cl)(=[O:14])[CH3:13].Cl>C(Cl)(Cl)(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([O:8][CH3:9])=[C:6]([C:12](=[O:14])[CH3:13])[CH:7]=1
Reactant: COc1ccc(Cl)c(OC)c1
Reactant: CC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(OC)c(C(C)=O)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
A mixture of 2 g of 1-chloro-2,4-dimethoxybenzene and 0.9 g of acetyl chloride in 20 ml of CCl4 is cooled to 0° C., and a solution of 1.3 ml of TiCl4 in 7 ml of CCl4 is added dropwise. The reaction mixture is left stirring for 2 hours while the temperature is allowed to rise to r.t. It is poured into a mixture of concentrated HCl and ice, the resulting mixture is extracted with DCM, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under vacuum. The residue is chromatographed on silica H, eluting with a DCM/heptane (70:30; v/v) mixture. 1.19 g of the expected product, m.p.=138° C., are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]5)=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][CH2:47][CH3:48].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][N:36]([CH2:46][CH2:47][CH3:48])[CH2:35][CH2:34]5)=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCC1CCNCC1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1CCC(COc2cc3nccc(Oc4ccc(Nc5ccc(C(C)(C)C)cc5)cc4)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 7 %

Procedure:
(4-Tert-butylphenyl)-{4-[6-methoxy-7-(4-piperidinylmethoxy)-4-quinolyloxy]phenyl}amine (150 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Potassium carbonate (300 mg) and 1-bromopropane (0.15 ml) were then added to the solution, and the mixture was stirred at room temperature for 4 hr. Water and ethyl acetate were added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by thin-layer chromatography on silica gel using chloroform/acetone for development to give the title compound (12 mg, yield 7%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=S)[NH:6][NH2:7])[CH2:3][CH2:2]1.[Cl:9][CH:10]([C:16]([CH3:18])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>Cl>[ClH:9].[CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([CH3:18])[NH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)NC1CC1
Agent: Cl
Product: CCOC(=O)c1c(NC2CC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.5 %

Procedure:
A stirred slurry of 10.4 g (0.079 mole) of 4-cyclopropyl-3-thiosemicarbazide under nitrogen atmosphere was treated with 13 g (0.079 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 1 hr, treated with 30 mL of 2N ethanolic hydrogen chloride and heated to reflux. The reaction mixture was allowed to cool to ambient temperature while stirring for ~72 hr. the sulfur residue was removed by filtration and the filtrate concentrated in vacuo to an orange oil which solidified. Recrystallization twice from acetone gave 7.4 g of large blade-like crystals, after drying for 2 hr at 98° C. under reduced pressure, mp 147°-148.5° C. The filtrates gave an additional 6 g of crude product. The 2 solids were combined and recrystallized from methyl ethyl ketone to give 6.3 g of white crystalline powder, mp 151°-152° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)/[C:7]1=[O:23])=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[N:32][C:33]([O:35][Si](C)(C)C)=[CH2:34])[CH:28]=[CH:29][CH:30]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C@:8]2([C@@H:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:35][C:33](=[O:34])[NH:32][C@H:31]2[C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)[C:7]1=[O:23])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\C2CCCCC2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)[C@]2(c3ccc(Cl)cc31)[C@@H](C1CCCCC1)CC(=O)N[C@H]2c1cccc(Cl)c1
Yield: 32 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-cyclohexylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.40 g, 1.20 mmol) was reacted with 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b, in toluene to give racemic ((2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-cyclohexyl-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester as a yellow oil (Yield 0.2 g, 32%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][N:26]=[C:25]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:25]2[C:24]3[C:28](=[C:20]([F:19])[CH:21]=[CH:22][CH:23]=3)[NH:27][N:26]=2)[C:3]2[CH:18]=[CH:17][N:16]=[CH:15][C:4]=2[N:5]=1
Reactant: Clc1ccccc1-c1nc(Cl)c2ccncc2n1
Reactant: Nc1n[nH]c2c(F)cccc12
Product: Fc1cccc2c(Nc3nc(-c4ccccc4Cl)nc4cnccc34)n[nH]c12

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[3,4-d]pyrimidine (100 mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (48.7 mg, 22% yield). HPLC-Method A, Rt 3.35 min; 1HNMR (DMSO, 500 MHz): δ 12.95 (1H, s), 10.90 (1H, bs), 9.25 (1H, s), 8.75 (1H, m), 8.55 (1H, m), 7.70-7.35 (5H, m), 7.25(1H, m), 6.95 (1H, m),; MS (m/z), MH+ 391.08.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:21])[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=1.Cl.[CH3:23][C@@H:24]1[CH2:29][O:28][CH2:27][CH2:26][NH:25]1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH3:21][N:3]1[C:4](=[O:20])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:9]=2)[N:7]=[C:2]1[N:25]1[CH2:26][CH2:27][O:28][CH2:29][C@H:24]1[CH3:23]
Reactant: Cn1c(Cl)nc(-c2ccnc(-c3ccccc3)n2)cc1=O
Reactant: C[C@@H]1COCCN1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COCCN1c1nc(-c2ccnc(-c3ccccc3)n2)cc(=O)n1C
Yield: 89.2 %

Procedure:
A solution of 2-chloro-1-methyl-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (149 mg, 0.50 mmol), (3R)-3-Methyl-morpholine hydrochloride (83 mg, 0.82 mmol), and diisopropylethylamine (0.313 ml, 1.8 mmol) in N,N-dimethylformamide (2.0 ml) was stirred at 80° C. Water was added to the solution and the precipitate was filtered, washed with water and diethyl ether, and dried to afford 1-methyl-2-((3R)-3-methyl-morpholin-4-yl)-2′-phenyl-1H-[4,4′]bipyrimidinyl-6-one (162 mg, quant.).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([N:19]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:18]2)[N:14]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:13][CH:12]3[CH3:40])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].NN>C(O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:30][CH:15]([CH2:16][CH:17]([NH2:19])[CH2:18]2)[N:14]([CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:13][CH:12]3[CH3:40])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)N(CCCc2ccccc2)CC3C)c1
Agent: NN
Solvent: CCO
Product: CC(C)Oc1cccc(C23CC(N)CC(C2)N(CCCc2ccccc2)CC3C)c1
Yield: 96.8 %

Procedure:
2-[5-(3-Isopropoxy-phenyl)-4-methyl-2-(3-phenyl-propyl)-2-aza-bicyclo[3.3.1]non-7-yl]-isoindole-1,3-dione (3.16 g, 7.8 mmol) and hydrazine (1.4 g, 43,7 mmol) were dissolved in ethanol (150 ml) and refluxed overnight. The solution was then cooled and the white percipitate was filtered and washed with cold ethanol. The solution was concentrated in vacuu and the crude material taken up in 3;1 CH2Cl2:THF. The resulting white percipitate was filtered and washed with cold CH2Cl2. The organic layer was concentrated to yield 3.07 g (97%) of the desired product as a yellow soild. 1H NMR (CDCl3) 7.18 (m, 6H), 6.71 (m, 3H), 4.56 (sept., J=6, 1H), 3.51 (m, 1H), 3.19 (br, 1H), 2.82 (m, 1H), 2.66 (m, 3H), 2.50 (m, 2H), 2.34 (m, 3H), 2.11 (m, 1H), 1.82 (m, 2H), 1.80 (m, 1H), 1.29 (d, J=6 Hz, 6H), 0.90 (m, 2H), 0.71 (d, J=7.2, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Br:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:32][CH2:31][C:30]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:29]2=[O:38])=[CH:25][CH:24]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH2:19][N:35]2[CH2:34][CH2:33][C:30]3([C:29](=[O:38])[N:28]([CH2:27][C:26]4[CH:25]=[CH:24][C:23]([Br:22])=[CH:40][CH:39]=4)[CH2:32][CH2:31]3)[CH2:37][CH2:36]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(C=O)C(c2ccccc2)C1
Reactant: O=C1N(Cc2ccc(Br)cc2)CCC12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(CN2CCC3(CC2)CCN(Cc2ccc(Br)cc2)C3=O)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To 275.3 mg (1 mmol) of 3-(RS)-formyl-4-(SR)-phenylpyrrolidine-1-carboxylic acid tert-butyl ester and 359.1 mg (1 mmol) of 2-(4-bromobenzyl)-2,8-diaza-spiro[4.5]decan-1-one hydrochloride were added 20 mL of DCE and 139 μL (1 mmol) of triethylamine. The reaction mixture was agitated for 10 minutes at room temperature before adding 334 mg (1.5 mmol) of triacetoxyborohydride. After an overnight agitation, 10 mL of saturated solution of sodium bicarbonate were added and the solution was extracted with DCM. The organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The crude yellow oil was purified by flash chromatography on silica gel (DCM/methanol 0% to 2%) giving Compound 1 as a colorless solid (520 mg, 89.3%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:27])[CH:11]=2)[CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>O1CCCC1>[Br:27][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:3][OH:2])[CH:14]=[C:13]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:23])=[O:24])=[CH:18][N:17]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(C(=O)OC)cc3ccc(Br)cc23)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CO)cc3ccc(Br)cc23)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
To a solution of 6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalene-2-carboxylic acid methyl ester (280 mg, 0.63 mmol) in tetrahydrofuran (5 mL) was added a solution of diisobutylaluminum hydride (1 M in toluene, 1.3 mL, 1.3 mmol) dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred at room temperature (the total stirring time between −78° C. and room temperature was 3 hours). The reaction mixture was treated with an aqueous solution of potassium sodium tartrate tetrahydrate at 0° C., warmed to room temperature, and stirred at room temperature for 30 min. The resulting mixture was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) to give [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-methanol (263 mg, 99%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11]>C(OCC)C.O1CCCC1>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)[Mg]Cl
Reactant: O=Cc1ccc(I)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2.5 g 4-Iodobenzaldehyde are dissolved in 25 ml diethylether, cooled to 0° C. and treated dropwise with 6.0 ml of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane. The temperature is slowly raised to room temperature and the mixture is stirred for further 12 hours. Then the reaction is quenched by addition of half saturated aqueous ammonium chloride. The aqueous phase is twice extracted with ethylacetate and the combined organic phases are washed twice with saturated aqueous ammonium chloride and brine. After drying with magnesium sulphate the solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 100:0 to 40:60).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([C:8]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([C:8]([N:10]2[CH2:11][CH2:12][S:13][CH2:14][CH2:15]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCSCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)N2CCSCC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
To a stirred solution of 4-(4-nitrobenzoyl)thiomorpholine (1.26 g, 5 mmol) in ethanol (80 mL) and water (20 mL) was added NH4Cl (2.65 g) and heated to 80° C. To this heterogeneous reaction mixture at 80° C. was added iron powder (2.75 g) portion wise manner under a vigorous stirring in nitrogen atmosphere and the stirring was continued for 2 h. The reaction mixture was filtered through a Celite pad when hot and washed the pad with methanol. The filtrate was concentrated, diluted with water, extracted with CH2Cl2 (3×75 mL), dried (Na2SO4), filtered and concentrated. Finally dried under high vacuum to afford 1.11 g (100%) of the 4-(4-aminobenzoyl)thiomorpholine. 1H NMR (CDCl3, 300 MHz): δ 7.21 (d, 2H, J=8.4 Hz), 6.64 (d, 2H, J=8.1 Hz), 3.86 (br s, 6H), 2.64 (t, 4H, J=4.5 Hz); LCMS (m/z): 223 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:10]=[CH:9]2)=[CH:4][C:3]=1[F:22].N1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:33]([O:32][C:30]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][O:14][Si:15]([C:18]([CH3:19])([CH3:21])[CH3:20])([CH3:16])[CH3:17])[N:10]=[CH:9]2)=[CH:4][C:3]=1[F:22])=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N)c(F)c2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(NC(=O)OCc3ccccc3)c(F)c2)cn1
Temperature: -20 °C

Procedure:
1-Amino-4-(4-t-butyldimethylsilyloxymethylimidazol-1-yl)fluorobenzene (36.1 g) was dissolved in dry dichloromethane (450 ml), treated with pyridine (11.3 ml), then stirred under argon while cooling to −20° C. Benzyl chloroformate (17.7 ml) in dichloromethane (50 ml) was added dropwise, maintaining the temperature. The mixture was then allowed to warm to ambient temperature over 1 hour, then stirred for a further 1.5 hours. The mixture was diluted with aqueous sodium bicarbonate (250 ml), and the organic layer separated. A further extraction with dichloromethane (200 ml) was made, the combined organic layers dried over magnesium sulfate, and solvent evaporated. The resulting oil was re-evaporated with toluene, and purified by chromatography on silica (500 g) in a sinter column, eluting with a gradient from CH2Cl2 to 50% EtOAc in CH2Cl2. Evaporation, then re-evaporation with toluene gave solid product (51 g).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:16]([NH:18][C@@H:19]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:20]([OH:31])[CH2:21][C@@H:22]([C:27]([OH:30])([CH3:29])[CH3:28])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=O)(C)(C)C.Cl.[CH2:40]([C@H:47]([CH2:51][C:52](=[O:54])[CH3:53])[C:48]([OH:50])=O)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>O1CCOCC1>[CH2:40]([C@H:47]([CH2:51][C:52](=[O:54])[CH3:53])[C:48]([NH:8][C@H:9]([C:16]([NH:18][CH:19]([CH2:32][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]1)[CH:20]([OH:31])[CH2:21][CH:22]([C:27]([OH:30])([CH3:28])[CH3:29])[C:23]([NH:25][CH3:26])=[O:24])=[O:17])[CH2:10][C:11]1[N:12]=[CH:13][S:14][CH:15]=1)=[O:50])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CC(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: CNC(=O)[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C)C(C)(C)O
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CNC(=O)C(CC(O)C(CC1CCCCC1)NC(=O)[C@H](Cc1cscn1)NC(=O)[C@@H](CC(C)=O)Cc1ccccc1)C(C)(C)O
Reaction time: 3 h
Yield: 72.9 %

Procedure:
A mixture or 192 mg (0.35 mmoles) of (2S, 4S, 5S)-5-[N-(t-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]amino-6-cyclohexyl-4-hydroxy-2-(1-hydroxy-1-methylethyl)-N-methylhexanamide [prepared as described in Example 9(a)] in 2 ml of a 4N solution of hydrogen chloride in dioxane was stirred at room temperature under an atmosphere of nitrogen for 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. Diethyl ether was added to the residue, and the solvent was again removed by distillation under reduced pressure. The same operation was repeated, in total, three times. The resulting residue was dried by evaporation under reduced pressure for 8 hours, and was then suspended in 5 ml of anhydrous tetrahydrofuran. 86 mg (0.42 mmoles) of 2(R)-benzyl-4-oxopentanoic acid (prepared as described in Preparation 20) were then added to the suspension, after which 0.06 ml (0.40 mmoles) of diethyl cyanophosphate and 0.16 ml (1.15 mmoles) of triethylamine were added to the mixture, whilst ice-cooling and under an atmosphere of nitrogen. The mixture was then stirred for 3 hours, after which the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (using an 8:1 by volume mixture of methylene chloride and methanol as the developing solvent), to give 164 mg (yield 74%) of the title compound as an amorphous substance.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16]C)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 5 h
Yield: 92.8 %

Procedure:
Methyl 4'-methylbiphenyl-2-carboxylate (10.0 g, 44.2 mmol, 1 eq), 0.5N KOH in methanol (265.5 mL, 133 mmol, 3 eq), and water (50 mL) were mixed and refluxed under N2. After 5 hours, the solvent was removed in vacuo and water (200 mL) and ethyl acetate (200 mL) added. The aqueous layer was acidified with concentrated hydrochloric acid to a pH of 3 and the layers were separated. The aqueous phase was extracted with ethyl acetate (2×200 mL), the organic layers collected, dried (MgSO4) and the solvent removed in vacuo to yield 8.71 g of a white solid; m.p. 140.0-145.0. NMR (200 MHz, DMSO-d6) δ 7.72 (d, 1H, J=7Hz); 7.56 (t, 1H, J=7Hz); 7.45 (d, 1H, J=7Hz); 7.40 (t, 1H, J=7Hz); 7.25 (s, 4H); 2.36 (s, 3H). Anal. Calcd. for C14H12O2 ; C, 79.23; H, 5.70. Found: C, 79.22; H, 5.47.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br>CN(C)C=O>[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:8]([CH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH3:13])[OH:9]
Reactant: NO
Reactant: Cc1ccccc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1CN(O)Cc1ccccc1C
Yield: 58.2 %

Procedure:
The procedure of Example 1 is repeated using 21.2 g of sodium carbonate, 3.47 g of hydroxylamine hydrochloride and 18.51 g o-methylbenzyl bromide in 75 ml of dimethylformamide. Recrystallization from ethanol affords 7.01 g of the title hydroxylamine as a white solid, mp 90°-93° C.