Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.B.C1COCC1.N1C=CC=CC=1.CCOC(C)=O>C1COCC1>[NH2:3][CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1
Reactant: CON=C(Cc1ccc(F)cc1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-phenyl-1-ethanone-O-methyl oxime (1.34 g, 4.62 mmol) in 30 ml dry THF under nitrogen was added borane-THF complex (1.0M in THF, 23.1 ml, 23.1 mmol) and dry pyridine (10 ml) by syringe at 25° C. The resulting bi-phasic solution was refluxed with vigorous magnetic stirring for 16 hours. After the reaction was cooled to 25° C. and was quenched with 10% NaOH solution, hexanes (50 ml) were added and the layers were separated. The aqueous portion was extracted with hexanes again (40 ml). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to yield a cloudy colorless syrup (3.55 g, 66% yield for two steps). Rf : 0.24 (EtOAc).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH2:12])[N:4]=1.O.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:18][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH2:12])[N:4]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CCCCO
Agent: [Na]
Solvent: O
Product: CCCCOc1nc(N)c2[nH]cnc2n1
Temperature: 140 °C
Reaction time: 19 h
Yield: 76 %

Procedure:
After sodium (13.56 g, 590 mmol) was dissolved in n-butanol (480 ml), 2-chloroadenine (4.0 g, 23.59 mmol) was added thereto and the mixture was stirred at 140° C. for 19 hours. After the mixture was allowed to cool, water (400 ml) was added thereto and the mixture was stirred for 30 minutes. And then the organic layer was separated and concentrated. Water (400 ml) was added to the residue and the solution was neutralized with concentrated hydrochloric acid. The resulting precipitate was filtered and washed with ethanol to give the captioned compound (3.72 g, 17.97 mmol, yield 76%) as a white solid.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:33]=[C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:31](=[O:32])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH3:22])=[CH:19][CH:20]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2ccc(CC)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(4-ethylphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 12, Part C). The mixture is heated to reflux for 90 minutes, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al]([C:21]#[N:22])(CC)CC>C1COCC1>[OH:15][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:9][CH2:10]1)[C:21]#[N:22]
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: CC[Al](C#N)CC
Solvent: C1CCOC1
Product: N#CC(O)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-(phenylmethyl)-4-piperidinecarbaldehyde (2.35 g, 11.6 mmol)[prepared according to Alfaro-Lopez, J.; et al. J. Med. Chem. 1999, 42, 5359] in THF (160 mL) at 0° C. was added dropwise Et2AlCN (25 mL, 1M solution in toluene). After 1 h, the solution was partitioned between NaHCO3(sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4) and concentrated yielding the title compound as a yellow oil which was used directly without further purification: LCMS (ES) m/e 249 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:13])([O:11][CH3:12])[O:9][CH3:10]>>[C:8](=[O:11])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[O:9][CH3:10].[C:8](=[O:13])([O:11][C:12]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:1]=1)[O:9][C:10]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1.[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)OC
Solvent: Oc1ccccc1
Product: COC(=O)Oc1ccccc1
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
The same procedure was selected as in Example 1. However, the reactor used was a 20-tray bubble-cap tray column 2 m in length and 5 cm in diameter. 500 g/h of phenol and 0.5 mol % of poly[oxy(butylhydroxystannylene)] were added at the head of the column, 500 g/h of gaseous dimethyl carbonate were added at the foot of the column. After one pass through the column, 554 g/h of a bottom product of composition 23.2% by weight of methyl phenyl carbonate, 2.1% by weight of diphenyl carbonate and 74.7% by weight of phenol were obtained, which still contained the catalyst. After a second pass of this product in the manner described in Example 1, 615 g/h of a bottom product of composition 36.8% by weight of methyl phenyl carbonate, 9.1% by weight of diphenyl carbonate and 54.1% by weight of phenol were obtained. After a third column pass, 670 g/h of a bottom product of composition 45.5% by weight of methyl phenyl carbonate, 14.3% by weight of diphenyl carbonate and 40.2% by weight of phenol were obtained. This corresponds to a space-time yield for the formation of methyl phenyl carbonate and diphenyl carbonate, based on three column passes, of 0.034 kg 1-1 h-1. After the fourth pass of the bottom product, in which no dimethyl carbonate was conducted in counter-current, the bottom product had the composition 13.5% by weight of methyl phenyl carbonate, 50.7% by weight of diphenyl carbonate and 35.8% by weight of phenol, which gives a space-time yield for the formation of methyl phenyl carbonate and diphenyl carbonate, based on 4 column passes, of 0.032 g 1-1 h-1. Here also, the catalyst was not removed at any stage, but recycled in all passes with the bottom product. The bottom compositions were determined by gas chromatographic analysis (GC) as % by weight compositions.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@H:5]3[C@@H:22]([C@@:23]4([CH3:29])[CH2:24][CH2:25][C@H:26]([OH:28])[CH2:27][C:2]124)[CH2:21][CH2:20][C@@:19]1([CH3:30])[C@H:6]3[CH2:7][CH2:8][C@:9]1([OH:31])[C@H:10]([CH3:18])[CH2:11][CH2:12][C@@H:13]([CH3:17])[CH:14]([CH3:16])[CH3:15].[NH2:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1.C(O)CCC>COC(C)(C)C>[OH:1][C@:2]12[CH2:27][C@@H:26]([OH:28])[CH2:25][CH2:24][C@:23]1([CH3:29])[C@@H:22]1[C@H:5]([C@H:6]3[C@:19]([CH3:30])([CH2:20][CH2:21]1)[C@@:9]([OH:31])([C@H:10]([CH3:18])[CH2:11][CH2:12][C@@H:13]([CH3:17])[CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:7]3)[CH2:4][C@H:3]2[NH:32][CH2:33][CH2:34][C:35]1[N:39]=[CH:38][NH:37][CH:36]=1
Reactant: CC(C)[C@H](C)CC[C@@H](C)[C@@]1(O)CC[C@H]2[C@@H]3C[C@@H]4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@@]21C
Reactant: NCCc1c[nH]cn1
Solvent: COC(C)(C)C
Solvent: CCCCO
Product: CC(C)[C@H](C)CC[C@@H](C)[C@@]1(O)CC[C@H]2[C@@H]3C[C@@H](NCCc4c[nH]cn4)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Yield: 13 %

Procedure:
5,6α-epoxicampestane-3β,17-diol (6.8 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give (5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-campestane-3β,17-diol) as a white solid (5.7 g, 49%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 13% yield.
Reaction SMILES: C(O)(=O)[C@H](CC(O)=O)[OH:3].[C:10]([OH:18])(=[O:17])[CH:11]([CH2:13][C:14]([OH:16])=[O:15])[OH:12].C([O-])(=O)[C@H](CC([O-])=O)O.[K+:28].[K+]>>[OH2:3].[C:10]([O-:18])(=[O:17])[C@H:11]([CH2:13][C:14]([OH:16])=[O:15])[OH:12].[K+:28]
Reactant: O=C(O)CC(O)C(=O)O
Reactant: O=C(O)C[C@H](O)C(=O)O
Agent: O=C([O-])C[C@H](O)C(=O)[O-]
Agent: [K+]
Product: O
Product: O=C(O)C[C@H](O)C(=O)[O-]

Procedure:
As a result of our investigations, we have now found that when L-malic acid and potassium ion are dissolved in an aqueous solvent at a pH higher than 6.8, a malic acid salt contained in the solution exists substantially in the form of dipotassium L-malate and can not be crystallized out from the aqueous solvent. In this connection, however, we have also found that crystals of monopotassium L-malate monohydrate or crystals composed of L-malic acid and monopotassium L-malate are obtained by cooling an aqueous solution of L-malic acid and potassium ion at a pH of 6.8 or less. Namely, pure crystals of monopotassium L-malate monohydrate are obtained by cooling an aqueous solution of L-malic acid and potassium ion having a pH of 6.8 or less, to initiate crystallization of a potassium salt of L-malic acid, and continuing said crystallization at a pH of 5.3 to 6.8, especially at a pH of 5.3 to 6.5. On the other hand, when the crystallization step described above is continued at a pH lower than 5.3, the crystals obtained as the solid phase are composed of L-malic acid and monopotassium L-malate. Moreover, we have found that pure crystals of monopotassium L-malate monohydrate can also be prepared from impure crystals composed of L-malic acid and monopotassium L-malate by allowing said impure crystals to stand in a small amount of water at a pH of 5.3 to 6.8 until liquid-solid equilibrium is substantially achieved.
Reaction SMILES: Cl.[F:2][CH:3]1[CH2:6][NH:5][CH2:4]1.[F:7][C:8]([F:58])([F:57])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:49]([CH3:50])=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][C:41]=5[CH3:51])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=3)[C@H:20]2[CH3:56])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C>C1COCC1>[F:17][C:15]([F:16])([F:18])[C:13]1[CH:12]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[CH:33]=[C:34]([C:40]5[C:41]([CH3:51])=[CH:42][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:48][C:49]=5[CH3:50])[CH:35]=[N:36][C:37]=4[O:38][CH3:39])=[CH:30][N:29]=[C:28]([N:5]4[CH2:6][CH:3]([F:2])[CH2:4]4)[N:27]=3)[C@H:20]2[CH3:56])[CH:10]=[C:9]([C:8]([F:7])([F:58])[F:57])[CH:14]=1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(S(C)(=O)=O)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Reactant: FC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
3-Fluoroazetidine hydrochloride (26.7 mg, 0.239 mmol), methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(methylsulfonyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (INTERMEDIATE 44, 60 mg, 0.080 mmol), THF (800 μl) and triethylamine (55.6 μl, 0.399 mmol) were stirred at 100° C. for 10 minutes in the microwave reactor. Once complete, the reaction was partitioned between water and ethyl acetate. The organic was then washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by silica gel chromatography, eluting with 25-100% ethyl acetate/hexanes to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ8.15 (s, 1H), 68.02 (d, 1H), 67.89 (s, 1H), 67.80 (s, 2H), 67.74 (s, 2H), 67.28 (d, 1H), 65.71 (d, 1H), 65.51 (m, 0.5H), 65.40 (m, 0.5H), 64.71 (d, 1H), 64.45 (m, 3H), 64.30 (m, 2H), 64.00 (d, s, 4H), 63.93 (s, 3H), 62.14 (d, 6H), 60.74 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:7][C:6]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH:46]1[CH2:53][CH:52]2[N:54]([CH3:55])[CH:48]([CH2:49][CH2:50][CH2:51]2)[CH2:47]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:55][N:54]1[CH:48]2[CH2:49][CH2:50][CH2:51][CH:52]1[CH2:53][CH:46]([NH:45][C:18]([C:16]1[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]3[O:9][C:8]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)=[N:7][C:6]=13)=[O:20])[CH2:47]2
Reactant: COc1cc(C(=O)O)c2nc(-c3ccccc3)oc2c1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CC3CCCC(C2)N3C)c2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.9 %

Procedure:
A mixture of 6-methoxy-2-phenylbenzoxazole-4-carboxylic acid (100 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (134 mg, 0.70 mmol), 1-hydroxybenzotriazole (95 mg, 0.70 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (99 mg, 0.44 mmol) in DMF (3 mL) was stirred at room temperature for 10 min, then triethylamine (0.20 mL, 1.40 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (2×50 mL), brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-methoxy-2-phenylbenzoxazole-4-carboxamide (24 mg, 16%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.08 (br s, 1H), 8.21-8.19 (m, 2H), 7.81 (d, J=2.5 Hz, 1H), 7.59-7.54 (m, 3H), 7.23 (d, J=2.5 Hz, 1H), 4.65-4.55 (m, 1H), 3.93 (s, 3H), 3.25-3.10 (m, 2H), 2.70-2.55 (m, 5H), 2.27-2.00 (m, 3H), 1.65-1.55 (m, 3H), 1.35-1.20 (m, 2H); MS (ESI+) m/z 406 (M+H); HPLC>99% (AUC), tR=13.14 min.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH:22][CH:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][O:26][C:25]2[CH:34]=[CH:35][C:36]([CH2:38][CH2:39][OH:40])=[CH:37][C:24]1=2>N1C=CC=CC=1>[OH:22][CH:23]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[CH2:27][O:26][C:25]2[CH:34]=[CH:35][C:36]([CH2:38][CH2:39][O:40][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:37][C:24]1=2
Reactant: OCCc1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: OC1c2ccccc2COc2ccc(CCOC(c3ccccc3)(c3ccccc3)c3ccccc3)cc21
Temperature: 50 °C
Reaction time: 5 h
Yield: 64.9 %

Procedure:
In this process, 17.2 g of 11-hydroxy-2-(2-hydroxyethyl)-6,11-dihydrodibenz[b,e]oxepin is dissolved in 50 ml of pyridine. To the solution is added 30 g of triphenylchloromethane and the mixture is stirred at 50° C. for 5 hours. After adding water and stirring the mixture for 2 hours, the solvent is distilled away under reduced pressure. The mixture is extracted with 1000 ml of ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is distilled away under reduced pressure and the resultant residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate=3:1 ) to obtain 21.7 g of the desired product as a colorless amorphous.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Br:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[Br:9][CH2:10][C:11]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][C:1]=1[CH3:8])=[O:12]
Reactant: O=C(Cl)CBr
Reactant: Cc1ccc(C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C)c(C(=O)CBr)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
A mixture of 10.60 g (0.10 mol) of para-xylene and 16.53 g (0.105 mol) of α-bromoacetyl chloride in 300 mL of 1,2-dichloroethane was cooled in an ice bath under an atmosphere of dry N2 and treated portionwise with 14.15 g (0.106 mol) of aluminum chloride. The reaction mixture was stirred for 30 minutes at 0-5° C. and then for 2.5 hours at room temperature. The mixture was then poured onto ice and the aqueous layer was acidified with concentrated HCl. The organic layer was separated and the aqueous layer was extracted twice with methylene dichloride. The combined organic extracts were dried with brine solution and with magnesium sulfate. The solvent was evaporated to give 23.87 g of an amber oil which was for use in the next reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[NH:31][C:32]([C@@H:35]5[CH2:39][CH2:38][CH2:37][N:36]5[C:40](=[O:53])[C@H:41]([NH:48][C:49]([O:51][CH3:52])=[O:50])[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)=[N:33][CH:34]=4)=[CH:26][CH:25]=3)=[N:22][CH:23]=2)=[CH:16][N:17]=1)=O)(C)(C)C.CO>CCOCC>[CH3:52][O:51][C:49](=[O:50])[NH:48][C@H:41]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:40](=[O:53])[N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[C:32]1[NH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:21]3[N:22]=[CH:23][C:18]([C:15]4[NH:14][C:13]([C@@H:9]5[CH2:10][CH2:11][CH2:12][NH:8]5)=[N:17][CH:16]=4)=[CH:19][N:20]=3)=[CH:25][CH:26]=2)=[CH:34][N:33]=1
Reactant: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cn3)cc2)[nH]1)c1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5)[nH]4)cn3)cc2)[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Cold (0° C.) 4 NHCl in dioxanes (4 mL) was added via syringe to (S)-2-{5-[2-(4-{2-[(S)-1-((R)-2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-pyrimidin-5-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (104.6 mg, 0.146 mmol) in a 100 mL pear-shaped flask followed by MeOH (0.5 mL). The homogeneous mixture was stirred at room temperature for 15 min before a precipitate was observed. After stirring further for 1.75 h, the suspension was diluted with ether and hexanes. Suction-filtration of a small portion of the suspension yielded the title compound as a yellow solid which was used for characterization purposes. The balance of the suspension was concentrated down to dryness and placed under high vacuum for 16 h. There was isolated the rest of the title compound also as a yellow solid (137.7 mg, 123%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OCCCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenyl-1-propanol and DBU in dioxane. ES-MS m/e (%): 376 (M{81Br}+H+, 98), 374 (M{79Br}+H+, 100), 258 ([M{81Br}+H-BnCH═CH2]+, 55), 256 ([M{81Br}+H-BnCH ═CH2]+, 50).
Reaction SMILES: O[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7].Cl[Si](C)(C)C.[I-].[Na+].C(#N)C>CCCCCC.O>[F:16][C:15]([F:17])([F:18])[C:11]1[CH:10]=[C:9]([CH:2]([CH3:8])[CH2:3][CH2:4][CH2:5][C:6]#[N:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(O)(CCCC#N)c1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CC#N
Product: CC(CCCC#N)c1cccc(C(F)(F)F)c1
Yield: 46.3 %

Procedure:
Under a nitrogen atmosphere, a solution of 4.4 grams (0.017 mole) of 5-hydroxy-5-(3-trifluoromethylphenyl)hexanenitrile, 13 mL (0.102 mole) of chlorotrimethylsilane, 15.4 grams (0.102 mole) of sodium iodide, and 8.0 mL (0.153 mole) of acetonitrile in 30 mL of hexane was stirred for about 30 minutes. After this time, gas chromatographic analysis of the reaction mixture indicated that the reaction was complete. The reaction mixture was then stirred with 100 mL of water, and then it was extracted with 100 mL of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The methylene chloride eluate was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 1.9 grams of 5-(3-trifluoromethylphenyl)hexanenitrile. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:18][CH2:17][C@H:16]([S:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH:11]=[CH:12]/[C@H:13]2[CH2:14][CH2:15][C@H:16]([S:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[O:38])[CH2:17][CH2:18]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(/C=C/C=C/[C@H]2CC[C@H](SCc3ccc(Cl)cc3)CC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=S(Cc1ccc(Cl)cc1)[C@H]1CC[C@H](/C=C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.08 h

Procedure:
In 20 ml of methylene chloride were dissolved 211 mg (0.48 mmol) of 4-chlorobenzyl trans-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadienyl]cyclohexyl sulfide, and 104 mg (0.48 mmol) of m-chloroperbenzoic acid (purity: 80%) were added to the solution at 0° C., followed by stirring of the resulting mixture for 5 minutes. An aqueous sodium sulfite solution and ethyl acetate were added to the reaction mixture and the organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous NaCl solution. After the mixture was dried, the crude product obtained by evaporation of the solvent was recrystallized from a mixed solvent of ethyl acetate-hexane to obtain 168 mg (yield: 77%) of the title compound having a melting point of 212 to 214° C.
Reaction SMILES: [OH-].[Na+].CS(C)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]#[N:16])=[CH:10][CH:9]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: BrCCCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: N#CC(CCCc1ccccc1)c1ccc(Cl)cc1

Procedure:
2 ml of an aqueous sodium hydroxide (1.08 g) solution was added to a 10 ml solution of dimethylsulfoxide containing 1.0 g (6.6 mmole) of 4-chlorophenylacetonitrile and 1.3 g (6.6 mmole) of 1-bromo-3-phenylpropane at room temperature. After stirring for 2 hours under the same conditions, water was added to the reaction mixture and the mixture was extracted with 10 ml of n-hexane, dried, and condensed under reduced pressure to obtain 1.78 g (yield: quantitative) of 2-(4-chlorophenyl)-5-phenylvaleronitrile.