Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][C@H:6]1[N:13]1[CH:20]=[CH:19][C:17]([NH2:18])=[N:16][C:14]1=[O:15])[CH2:2][CH3:3].[Cl-].[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>O.N1C=CC=CC=1>[C:22]([NH:18][C:17]1[CH:19]=[CH:20][N:13]([C@@H:6]2[O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:5]2[O:4][CH2:1][CH2:2][CH3:3])[C:14](=[O:15])[N:16]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=O
Reaction time: 0.5 h

Procedure:
To the 2′-O-propylcytidine reaction mixture of Example 82 in an ice bath was added pyridine (60 ml) and trimethylsilIyl chloride (60 ml). The reaction was stirred for 30 mins followed by the addition of benzoyl chloride (55 ml). The resulting reaction mixture was stirred for 2.5 hr. and then cooled in an ice bath. H2O (100 ml) and conc. NH4OH (100 ml) were added. After stirring for 30 mins, the reaction mixture was evaporated and the residue partition between H2O and CH2Cl2. The organic phase was washed once with dil Na2CO3, once with dil HCl, dried over MgSO4 and evaporated. The resulting residue was loaded on a silica gel column (150 g) and eluted with first CH2Cl2 then 5 to 10% MeOH in CH2Cl2 as the elution solvent. The product containing fractions were evaporated to a foam. The foam was crystallized from EtOAc/Hexanes to give the product (6.5 g total) in several crystal batches.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]([CH3:10])[C:8](=[O:11])[NH:7][C:6](=[O:12])[CH:5]=1.[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21]Cl)(=[O:15])[CH3:14].[Cl-].[Na+]>CS(C)=O>[C:13]([O:16][C@H:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][N:7]1[C:6](=[O:12])[CH:5]=[C:4]([NH2:3])[N:9]([CH3:10])[C:8]1=[O:11])(=[O:15])[CH3:14]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: CC(=O)O[C@H](C)CCCCCl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(=O)O[C@H](C)CCCCn1c(=O)cc(N)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirring suspension of sodium hydride (5.52 g, 230 mmol) in anhydrous dimethylsulfoxide (500 ml) was added 6-amino-1-methyluracil (28.2 g, 200 mmol). After stirring at room temperature under argon for 2 hours, (R)-5-Acetoxy-1-chlorohexane (37.5 g, 210 mmol) was added neat and the mixture was stirred at 80° C. for 16 hours. After cooling to room temperature, the mixture was poured into saturated aqueous sodium chloride solution (1500 ml) and extracted with ethyl acetate (9x 200 ml). The combined extracts were washed with water (2x 50 ml), with saturated aqueous sodium chloride solution (50 ml) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting oil was treated with ethyl ether (400 ml). After stirring overnight at room temperature, the precipitate was filtered and rinsed with ether (2x 50 ml) to provide (R)-3-(5-acetoxyhexyl)-6-amino-1-methyluracil (44.0 g, 78% yield) as a beige powder.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCO>[OH:14][C@@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@]1(C)O
Temperature: 110 °C
Reaction time: 12 h
Yield: 69.4 %

Procedure:
To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (76 mg, 0.26 mmol) and tert-butyl [(3R,4S,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (60 mg, 0.24 mmol), EtOH was added (2.0 mL), followed by DIPEA (114 mg, 0.883 mmol). The mixture was stirred at 110° C. for 12 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow foamy solid (68 mg, 69%). LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. found 409.0.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.[C:23]1([CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[OH:24]>C(O)CCC.[Na].[Hg]>[CH2:21]([O:24][C:23]1[CH:30]=[CH:29][C:27]([OH:28])=[CH:26][CH:25]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [Hg]
Agent: [Na]
Solvent: CCCCO
Product: C=CCCCCCCCCCOc1ccc(O)cc1
Temperature: 110 °C
Reaction time: 7 h
Yield: 47.6 %

Procedure:
2.60 g (8.02 mM) of 10-undecenyl p-toluenesulfonate and 1.79 g (16.2 mM) of hydroquinone were well mixed with 3 ml of butanol under stirring. Into the solution, a solution of 0.419 (9.74 mM) of sodium amalgam dissolved in 6 ml of butanol, followed by 7 hours of heat-refluxing at 110° C. After the reaction, butanol was distilled off, followed by addition of water and extraction with ether. To the ether extract liquid was added anhydrous sodium sulfate for drying, followed by distilling-off of ether and purification by column chromatography (developer solvent: methylene chloride) to obtain 1.00 g (3.82 mM) of p-(10-undecenyl)oxyphenol. Yield: 47.6%.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[CH:15][N:14]=1.CO>O>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:11]=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)[C:16]([CH3:20])=[CH:15][N:14]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)nc1Nc1ccc2[nH]c(=O)oc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
To a vial with 6-aminobenzo[d]oxazol-2(3H)-one (1.0 g, 6.7 mmol) and 2,4-dichloro-5-methylpyrimidine (1.4 g, 8.7 mmol), solvents MeOH (20 mL) and H2O (5 mL) were added. The turbid mixture was stirred at room temperature for 2 days. Precipitate from the reaction mixture was collected by filtration, washing with H2O (3 mL×2) and EtOAc (3 mL×2), and was further drying in vacuo. 6-(2-Chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as a light tan color solid: 1.59 g (86% yield); 1H NMR (300 MHz, DMSO) δ 11.59 (s, 1H), 8.87 (s, 1H), 7.99 (s, 1H), 7.56 (s, 1H), 7.28 (d, J=8.3, 1H), 7.06 (d, J=8.3, 1H), 2.14 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][CH:5]([CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)[CH2:6][CH2:7][CH:8]=1)=[CH2:2].NN.[OH2:17].OO>C(O)C>[CH2:1]([C:3]1[CH2:4][CH:5]([CH2:9][C:10]2[NH:11][C:12](=[O:17])[NH:13][CH:14]=2)[CH2:6][CH2:7][CH:8]=1)[CH3:2]
Reactant: O
Reactant: C=CC1=CCCC(Cc2c[nH]cn2)C1
Agent: NN
Agent: OO
Solvent: CCO
Product: CCC1=CCCC(Cc2c[nH]c(=O)[nH]2)C1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of NiCl2 (0.364 g, 2.81 mmol) in EtOH (20 mL) was reacted with NaBH4 (0.053 mg, 1.40 mmol) at rt for 15 m after saturation of the solution with hydrogen gas. Ethylene diamine (0.17 g, 2.81 mmol) was added followed by the alkynyl imidazol (Intermediate R15, 0.26 g, 1.40 mmol) at rt for 45 m under an atmosphere of hydrogen gas. The mixture was filtered, diluted with chloroform and subjected to an aqueous work-up. The residue was purified by chromatography on SiO2 to give 4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (72%). To 4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (0.09 g, 0.47 mmol) in ethanol (3 mL) at 0° C. was added H2NNH2.H2O (0.93 mL, 19.1 mmol) followed by H2O2 (30%) (0.488 g, 14.4 mmol) and the mixture was stirred for 45 m at 0° C. and an additional 6 h at rt. The reaction was quenched and the material was purified by an aqueous work-up. The imidazole compound was purified further by isolation of the fumaric acid salt. The fumarate was converted to the compound 4-(3-ethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 59) by the applicable step of Method P.
Reaction SMILES: [C:1](OCC)(=[O:5])[C@H:2]([CH3:4])[OH:3].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[OH:3][C@@H:2]([CH3:4])[C:1]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:5]
Reactant: CCOC(=O)[C@H](C)O
Reactant: C1COCCN1
Product: C[C@H](O)C(=O)N1CCOCC1
Temperature: 80 °C
Yield: 68.7 %

Procedure:
A mixture of (S)-ethyl lactate (75 g) and morpholine (164 g) was heated at 80° C. for 64 hours. The reaction solution was concentrated and the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=4/1 to ethyl acetate) to give 4-[(S)-2-hydroxypropionyl]-morpholine (69.4 g) as a pale yellow oily substance. p-Toluenesulfonic acid monohydrate (0.82 g) was added to a solution of 4-[(S)-2-hydroxypropionyl]morpholine (69.4 g) in dichloromethane (300 ml), to which 3,4-dihydro-2H-pyran (40.3 g) was added dropwise at ice-bath temperature. The reaction solution was stirred at 0° C. for 30 minutes and washed with a 5% aqueous solution of sodium bicarbonate. After the organic layer was dried over anhydrous magnesium sulfate and concentrated, the residue was subjected to silica gel chromatography (eluent: hexane/ethyl acetate=8/1 to ethyl acetate) to give 4-[(2S)-2-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (89.1 g) as a pale yellow oily substance.
Reaction SMILES: Cl.[NH2:2][NH2:3].CCO/[CH:7]=[CH:8]/[C:9]([C:11]([F:14])([F:13])[F:12])=O.FC(F)(F)C(Cl)=O.C(OCC)=C>CO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[CH:7][NH:3][N:2]=1
Reactant: CCO/C=C/C(=O)C(F)(F)F
Reactant: NN
Agent: C=COCC
Agent: Cl
Agent: O=C(Cl)C(F)(F)F
Solvent: CO
Product: FC(F)(F)c1cc[nH]n1

Procedure:
To a solution of 4.4 moles hydrazine.hydrochloride in 2.2 L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel an equimolar amount of ETFBO which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether was added dropwise over about 4 hours under N2 atmosphere. The temperature of the reaction mixture was kept below 15° C. After 12 h of reflux, the reaction batch was filtered in a 2 L flask and concentrated under vacuum (An identical batch was made under the same conditions, yield of both crude products was ca. 95%). Subsequently, the combined crude product was purified by shortpass-vacuum distillation at 27 mbar. The yield was 1105 g, which corresponded to 92% of the theoretical yield.
Reaction SMILES: [CH3:1][C:2]([OH:19])([CH2:4][CH2:5][Si:6]([Si:15]([CH3:18])([CH3:17])[CH3:16])([Si:11]([CH3:14])([CH3:13])[CH3:12])[Si:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].O1CCCC1.C(N(CC)CC)C.[C:32](Cl)(=[O:36])[C:33]([CH3:35])=[CH2:34]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CCCCC>[CH3:35][C:33](=[CH2:34])[C:32]([O:19][C:2]([CH3:1])([CH2:4][CH2:5][Si:6]([Si:15]([CH3:16])([CH3:18])[CH3:17])([Si:7]([CH3:10])([CH3:9])[CH3:8])[Si:11]([CH3:14])([CH3:13])[CH3:12])[CH3:3])=[O:36]
Reactant: CC(C)(O)CC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Reactant: C=C(C)C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(C)(C)CC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Yield: 67.5 %

Procedure:
A dried reaction flask equipped for magnetic stirring was flushed with nitrogen and charged with 2,6,6-trimethyl-5,5-bis(trimethylsilyl)-5,6-disilaheptan-2-ol (53.6 g, 160 mmol, prepared as described in Example 1) and dry tetrahydrofuran (400 mL). Triethylamine (78.1 mL, 56.7 g, 560 mmol) and methacryloyl chloride (54.7 mL, 58.5 g, 560 mmol) were added, and the reaction mixture was stirred at room temperature for 24 hours. Analysis of the reaction mixture by gas chromatography indicated the clean formation of a single product. Pentane (500 mL) was added, precipitated triethylamine hydrochloride was separated by filtration, and the filtrate was concentrated under reduced pressure. The turbid concentrate was dissolved in pentane (500 mL), the resultant solution was filtered and concentrated under reduced pressure, and 2,6-di-tert-butyl-4-methylphenol (0.50 g, 2.3 mmol) was added to the concentrate. The concentrate was distilled under vacuum (bp 120-130° C. at 0.05 mm) to afford the title compound (43.5 g, 67%) as a clear, colorless liquid. The distilled product was characterized by the following NMR data: 1H NMR (CDCl3) δ 0.13 (s, 27 H), 0.70-0.80 (m, 2 H), 1.43 (s, 6 H), 1.75-1.85 (m, 2 H), 1.87 (s, 3 H), 5.43 (m, 1 H), 5.96 (m, 1 H); 13C NMR (CDCl3) δ 0.78 (1 C), 0.99 (9 C), 18.30 (1 C), 25.19 (2 C), 40.25 (1 C), 82.83 (1 C), 123.89 (1 C), 137.85 (1 C), 166.36 (1 C); 29Si NMR (CDCl3) δ −81.26 (1 Si), −12.80 (3 Si).
Reaction SMILES: [C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH:10]=2)[NH2:2].C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].C(Cl)(Cl)Cl>O.CO>[C:1](=[O:26])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[N:15]3[C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[C:11]2[C:6]1=[C:7]([OH:25])[CH:8]=[C:9]([CH:20]([O:23][CH3:24])[O:21][CH3:22])[CH:10]=2)[NH2:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(OC)c1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2COC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: COC(OC)c1cc(O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(O)(O1)C2COC(N)=O

Procedure:
6,9-Dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (22 mg) and sodium bicarbonate (12 mg) were dissolved in water (0.5ml). To the solution was added benzyl chloroformate (0.02 ml) with stirring in an ice-water bath. The mixture was stirred for 30 minutes in an ice-water bath and subjected to preparative thin layer chromatography. Development was carried out with a mixture of chloroform and methanol to afford 11-benzyloxycarbonyl-6,9-dihydroxy-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (15 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:12](=O)[CH2:13][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])(=O)C.[NH4+:35]>C(O)(=O)C.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:12]2[NH:35][C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:14][CH:13]=2)[CH2:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: [NH4+]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ccccn2)cc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3ccccn3)[nH]2)cc1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 85.7 %

Procedure:
To a solution of 5-[4-(methylsulfonyl)phenyl]-1-(pyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (525 mg) in acetic acid (6 mL) was added ammonium acetate (1.50 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (430 mg, yield 86%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 411 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C[Si]([C:22]#[N:23])(C)C.C(Cl)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:22]#[N:23])[CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cc2cc[n+]([O-])cc2)cc1
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: N#Cc1cc(Cc2ccc([N+](=O)[O-])cc2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 34.3 %

Procedure:
To a solution of 4-(4-nitro-benzyl)-pyridine 1-oxide (1.0 g, 4.3 mmol) in dichloromethane (9 mL) was added-trimethylsilyl cyanide (2.3 mL, 17 mmol). After 5 min, benzoyl chloride (1.0 mL, 8.7 mmol) was added dropwise and the mixture was stirred at rt for an additional 30 min. Water (10 mL) was carefully added, followed by solid potassium carbonate (2.1 g). After 30 min, the aqueous phase was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography, eluting with 5-25% ethyl acetate in hexanes, gave an orange oil. This oil was subsequently triturated with toluene to afford 4-(4-nitro-benzyl)-pyridine-2-carbonitrile as a tan solid (353 mg, 34%). 1H NMR (CHCl3-d) δ 8.63 (d, J=4.8 Hz, 1H), 8.21 (m, 2H), 7.49 (m, 1H), 7.32 (m, 3H), 4.15 (s, 2H).
Reaction SMILES: [C:1]([C:5]1[C:13]2S[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.CC[O:27]C(C)=O>CCO>[NH2:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:13]2[O:27][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=2[CH:8]=1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])cc2c1SCC2(C)C
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reaction time: 3 h

Procedure:
A suspension of 7-tert-butyl-2,3-dihydro-3,3-dimethyl-5-nitro-benzothiophene (2.6 g, 8.8 mmol) in absolute EtOH (60 mL) is hydrogenated at 40 psi of H2 pressure on a Parr hydrogenation apparatus for 3 h at 22° C. The reaction is judged complete by TLC (hexane:EtOAc, 19:1; visualized with Dragendorff reagent). The reaction mixture is filtered through Celite and evaporated to yield the title compound as a purple solid, which is used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([C@@H:18]([NH:22][C:23](=O)OC(C)(C)C)[C@H:19]([OH:21])[CH3:20])=[N:17][C:13]=2[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[NH3:15].[C:7]([C:11]1[CH:31]=[CH:30][C:14]2[NH:15][C:16]([C@@H:18]([NH:22][CH3:23])[C@H:19]([OH:21])[CH3:20])=[N:17][C:13]=2[CH:12]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](c1nc2cc(C(C)(C)C)ccc2[nH]1)[C@@H](C)O
Product: N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of 2M Lithium aluminum hydride in THF (0.09 mL, 0.180 mmol) was added a solution of the intermediate product from Example 78, Step 1; tert-butyl [(1R,2R)-1-(5-tert-butyl-1H-benzimidazol-2-yl)-2-hydroxypropyl]carbamate (50 mg, 0.15 mmol) in THF (2 mL) dropwise at 0° C. The reaction mixture was then refluxed for 18 hours. The reaction was cooled, quenched by the addition of Na2SO4.10H2O portionwise followed by anhydrous Na2SO4 and THF (5 mL) and stirred at room temperature for 30 minutes. The suspension was filtered through arbocel and the filtrated concentrated in vacuo. The residue was purified using silica gel column chromatography twice eluting both times with 90:10:1 DCM:MeOH:NH3 to afford the title compound.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.Cl[C:9](=[N:15][OH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].O.[Cl:18]CCl>ClC(Cl)=C>[Cl:18][C:6]1[O:16][N:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: ClCCl
Reactant: CCN(CC)CC
Solvent: O
Solvent: C=C(Cl)Cl
Product: CCOC(=O)c1cc(Cl)on1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 39 %

Procedure:
A mixture of triethylamine (13.12 mL; 90.73 mmol) in 1,1-dichloroethene (75 mL) was added to ethyl 2-chloro-2-(hydroxyimino)acetate (5.5 g; 36.29 mmol) in 1,1-dichloroethene (50 mL) over a period of 2 h the reaction mixture was stirred at room temperature for 20 min and portioned between water (75 mL) and dichloromethane (75 mL). The aqueous were extracted with dichloromethane, the organic layers rejoined were dried, concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in heptane) to afford ethyl 5-chloroisoxazole-3-carboxylate 2.5 g (39%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[C:3]1=[O:24].C(N(CC)CC)C.Cl[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:46])([F:45])[F:44])[CH:41]=2)[N:36]=[CH:35][N:34]=1>CCO>[CH:15]([N:13]([CH3:14])[C@@H:10]1[CH2:11][CH2:12][C@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:33]3[C:42]4[C:37](=[CH:38][CH:39]=[C:40]([C:43]([F:45])([F:46])[F:44])[CH:41]=4)[N:36]=[CH:35][N:34]=3)[C:3]2=[O:24])[C@H:8]([CH2:18][S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH2:9]1)([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCS(=O)(=O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 80 °C
Yield: 63 %

Procedure:
To a solution of (S)-3-amino-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)pyrrolidin-2-one (50 mg, 0.1 mmol) in EtOH (2 mL) was added triethylamine (0.1 mL, 0.6 mmol) and 4-chloro-6-(trifluoromethyl)quinazoline (27 mg, 0.11 mmol). The mixture was heated at 80° C. for 14 h and then concentrated in vacuo. The residue was pjurified by HPLC to provide the title compound, (S)-1-((1S,2R,4R)-4-(isopropyl(methyl)amino)-2-(ethylsulfonylmethyl)cyclohexyl)-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-2-one (35 mg). MS found: (M+H)+=556.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[Cl:6][CH2:7][CH2:8][C:9]#[N:10]>>[ClH:6].[S:1]([NH:5][C:9](=[NH:10])[CH2:8][CH2:7][Cl:6])(=[O:3])(=[O:2])[NH2:4]
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Product: Cl
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a suspension of 9.61 g. (0.10 mole) of sulfamide in 60 ml (68 g., 0.76 mole) of 3-chloropropionitrile dry hydrogen chloride gas is introduced under stirring at 50° to 60° C. for 5 hours. The gain in weight is about 9 to 12 g. The reaction mixture is then cooled with ice water for one hour, the product is filtered off, washed twice with acetone and dried up to steady weight.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Cl:11]Cl>C(Cl)Cl>[Cl:11][C:5]1[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]=1[CH3:9]
Reactant: ClCl
Reactant: CC1=CC(=O)OC(C)(C)O1
Solvent: ClCCl
Product: CC1=C(Cl)C(=O)OC(C)(C)O1
Temperature: 20 °C
Yield: 100 %

Procedure:
A solution of 2,2,6-trimethyl-1,3-dioxin-4-one (0.2 mol, 28.4 g) in 100 ml of CH2Cl2 was cooled to -50° C. and liquid chlorine (0.25 mol) was added dropwise over five minutes. The solution was allowed to warm to 20° C. over 30 minutes, and the solvent was then removed in vacuo, leaving 35.8 g (100% yield, 92% assay) of a pale yellow oil. A portion of this mixture was purified by flash chromatography (10% Et2O/hexanes on silica) to provide the title compound as white crystals.