Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]=[C:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]([O:16][CH3:17])=[O:15].[I:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1>C(#N)C.O>[I:23][C:24]1[CH:25]=[N:26][N:27]([CH2:12][CH:13]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:14]([O:16][CH3:17])=[O:15])[CH:28]=1
Reactant: C=C(CC(=O)OC)C(=O)OC
Reactant: Ic1cn[nH]c1
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CC(Cn1cc(I)cn1)C(=O)OC
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (753 mg, 3 mmol) was added to a stirred mixture of dimethyl 2-methylenesuccinate (158 mg, 1.00 mmol) and 4-iodo-1H-pyrazole (194 mg, 1.00 mmol) in acetonitrile (2 mL) and the mixture was stirred at room temperature under N2 for 12 hours. The mixture was diluted with water and extracted with EtOAc. The EtOAc layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC on silica gel (petroleum ether/EtOAc) to afford dimethyl 2-((4-iodo-1H-pyrazol-1-yl)methyl)succinate. MS ESI calcd. for C10H14IN2O4 [M+H]+ 353, found 353. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.39 (s, 1H), 4.55-4.36 (m, 2H), 3.72 (s, 3H), 3.68 (s, 3H), 3.42-3.33 (m, 1H), 2.70-2.47 (m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([CH3:17])[C:11](=[O:18])[C:10]=1[CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25].[O-:32][C:33]#[N:34].[K+].FC(F)(F)C(O)=O>O>[C:33](=[O:32])([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]([C:10]1[C:11](=[O:18])[C:12]([CH3:17])=[C:13]([CH3:16])[C:14](=[O:15])[C:9]=1[CH3:8])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[NH2:34]
Reactant: CC1=C(C)C(=O)C(C(CCCCCO)c2ccccc2)=C(C)C1=O
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)C(C(CCCCCOC(N)=O)c2ccccc2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
Toluene (10 ml) was added to 1.20 g (3.68 mmole) of 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-phenylhexanol and 0.90 g (3.68×3 mmole) of potassium cyanate, followed by stirring at room temperature, and 1.38 g (3.68×3.3 mmole) of trifluoroacetic acid was added to the mixture over the 5-minutes period. 5 Minutes later, the reaction temperature was raised to 40° C., and stirring was effected at 35° to 40° C. for 3 hours. After water was added, the insoluble matter was filtered out, and isopropyl ether was added to the filtrate to effect extraction. The organic layer was separated out, washed with aqueous sodium chloride solution, dried (magnesium sulfate) and evaporated. The residue was chromatographed on a silica gel column to elute with isopropyl ether to give 0.79 g (58%, recrystallized from isopropyl ether) of 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-phenylhexyl carbamate. Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound No. 59 was prepared.
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:18]O>>[CH3:18][O:12][C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][C:2]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:11]2)=[CH:6][CH:7]=1
Reactant: CO
Reactant: O=C1CCc2ccc(O)cc2C1
Reactant: C1CCNC1
Product: COc1ccc2c(c1)C=C(N1CCCC1)CC2

Procedure:
Under N2 atmosphere, a solution of 7-hydroxy-3,4-dihydro-1H-naphthalen-2-one (85 g, 0.48 mol) and pyrrolidine (264 g, 1.5 mol) in MeOH (3000 mL) was stirred at room temperature for 2 hrs. The solvent was removed in vacuo to give crude 1-(7-methoxy-3,4-dihydro-naphthalen-2-yl)-pyrrolidine (320 g) which was directly used for next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[C:13]1[C:14](=[O:23])[CH:15]([CH2:20][C:21]#[CH:22])[CH2:16][C:17]=1[O:18]C>CC(C)=O.Cl.ClCCl.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([O:11][CH3:12])[C:3]=1[CH:13]1[C:14](=[O:23])[CH:15]([CH2:20][C:21]#[CH:22])[CH2:16][C:17]1=[O:18]
Reactant: C#CCC1CC(OC)=C(c2c(Cl)cc(C#CC)cc2OC)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: C#CCC1CC(=O)C(c2c(Cl)cc(C#CC)cc2OC)C1=O
Temperature: 25 °C

Procedure:
A solution of 2-(2-chloro-6-methoxy-4-prop-1-ynyl-phenyl)-3-methoxy-5-prop-2-ynyl-cyclopent-2-en-1-one (0.042 g, 0.1277 mmol) in acetone (1.5 mL) and 2M aqueous HCl (0.5 mL) was heated under microwave irradiation at 100°C. for 30 minutes. The reaction mixture was allowed to cool to room temperature, and then was diluted with dichloromethane (5 ml) and water (5 ml), and then was separated by elution through a phase separation cartridge, washing with more dichloromethane. The organic filtrate was evaporated to dryness under reduced pressure to give a yellow solid. The crude product was dissolved in dichloromethane and adsorbed onto silica and then purified by flash chromatography over silica using an EtOAc/isohexane gradient to give the desired product as a mixture of atropisomers. 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (s, 1H), 6.85 (s, 1H), 3.79 (s, 3H), 2.99-2.56 (m, 5H), 2.06 (s, 3H), 2.00 (s, 1H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([OH:23])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:27]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:1])=[C:17]([CH:16]=1)[O:23][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(OCc2ccccc2)cc1OCC(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A suspension of methyl triphenyl phosphonium bromide (MTPPB, 16.90 g, 47.31 mmol) in anhydrous THF (50 mL) was cooled in an ice bath and added with potassium tert-butoxide (t-BuOK, 5.31 g, 47.32 mmol) in portions under nitrogen. After stirring at 0° C. for 15 min, a mixture of 4-benzyloxy-2-hydroxybenzaldehyde (1)(9.0 g, 39.43 mmol), t-BuOK (4.87 g, 43.40 mmol) and THF (50 mL) was added, and the resultant mixture was stirred at 0° C. for 2 hrs. Thereafter, the mixture was heated under reflux, and a solution of 2-bromo-4′-methoxyacetophenone (10.85 g, 47.36 mmol) in THF (30 mL) was added dropwise. After stirring under reflux for 1 hr (TLC monitoring), the mixture was quenched with a saturated NH4Cl solution. After removal of most of the THF in vacuo, the resultant residue was extracted six times with EtOAc (50 mL). The organic layers were combined, washed with a saturated NaCl solution, and dried with anhydrous MgSO4. After filtration, the filtrate was concentrated in vacua, followed by purification via silica gel column chromatography (ethyl acetate/n-hexane=1:15), thus giving the title compound 2a as a colorless crystal (11.81 g, 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Cl:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:12]([O-])([OH:14])=[O:13]>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([Cl:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(Cl)cc1OC
Product: COc1cc(Cl)c([N+](=O)[O-])cc1OC
Reaction time: 1.5 h

Procedure:
Into a triple-necked flask of one liter, provided with a magnetic stirring system, with a thermometer and a dropping funnel, were introduced successively 143.9 g (0.83 mole) of 3,4-dimethoxy chlorobenzene, then drop by drop 166 cm3 of nitric acid (d=1.38), without the temperature exceeding 25° C. When the addition was ended, the reaction mixture was allowed to stand 1.5 h and then filtered.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[NH2:6][C:4]([C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cccc(N)c1C(N)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cccc(C)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 2-amino-6-methylbenzamide (1.28 g, 8.52 mmol) and triethylamine (1.03 g, 10.2 mmol) in THF (30 mL) was added dropwise ethyl chloroglyoxylate (1.28 g, 9.38 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in diisopropyl ether-ethanol, and the insoluble material was collected by filtration to give ethyl ((2-(aminocarbonyl)-3-methylphenyl)amino)(oxo)acetate as a white powder (1.85 g, 87%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[CH3:39][NH:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44]>>[OH:45][CH:42]([CH2:43][OH:44])[CH2:41][N:40]([CH3:39])[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: CNCC(O)CO
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN(C)CC(O)CO)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for Example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-methylamino-1,2-propanediol were converted to the title compound.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C@H:18]3[CH2:22][C@H:21]([OH:23])[C@@H:20]([CH2:24][OH:25])[CH2:19]3)[CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.Cl[S:42]([NH:45]C(=O)OC(C)(C)C)(=[O:44])=[O:43]>C(#N)C>[S:42](=[O:44])(=[O:43])([O:25][CH2:24][C@H:20]1[CH2:19][C@@H:18]([NH:17][C:13]2[CH:12]=[C:11]([NH:10][C@@H:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)[N:16]=[CH:15][N:14]=2)[CH2:22][C@@H:21]1[OH:23])[NH2:45]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CC#N
Product: NS(=O)(=O)OC[C@H]1C[C@@H](Nc2cc(N[C@H]3CCc4ccccc43)ncn2)C[C@@H]1O
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A neat mixture of (1S,2R,4R)-4-({6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]pyrimidin-4-yl}amino)-2-(hydroxymethyl)cyclopentanol (100. mg, 0.294 mmol) and 2,6-di-tert-butyl-4-methylpyridine (181 mg, 0.881 mmol) was dissolved in ACN (5.00 mL) before tert-butyl (chlorosulfonyl)carbamate (95.0 mg, 0.441 mmol, as prepared in Example 21c) was added. The reaction was stirred for 2 h before being quenched via addition of MeOH (2 mL). The resulting mixture was concentrated in vacuo and purified via silica gel chromatography eluting with a gradient of 10 to 20% MeOH in DCM to afford the title compound as an amorphous solid (50.0 mg, 33%). LC/MS: Rt=1.24 min, ES+ 520. (AA standard).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21].[CH3:23]I>CC(N(C)C)=O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:23])=[O:5])([O-:22])=[O:21]
Reactant: O=C(O)c1ccccc1S
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
A solution of 2-mercaptobenzoic acid (6.0 g, 39.0 mmol) in dimethylacetamide (20 mL) was added to a suspension of sodium hydride (60% in oil, 3.1 g, 77.5 mmol) in dimethylacetamide (15 mL). The mixture was stirred for 5 minutes and 1-fluoro-2-nitrobenzene (5.0 g, 35.5 mmol) was added. The reaction mixture was heated at 80° C. for one hour. The mixture was cooled down to room temperature and methyl iodide (7.3 mL, 117.15 mmol) was added. The reaction mixture was stirred at room temperature 16 hours. The mixture was then poor into water and extracted with a mixture of 75% ethyl acetate in hexanes (3 times). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was dissolved in a minimum amount of dichloromethane and hexanes was added to precipitate the product. The solid was filtered and dried to afford title compound 408 (7.81 g, 76%) as a yellow solid. MS (m/z): 312.2 (M+H).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].CC([O-])=O.[Na+].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[C:15]([F:21])[CH:14]=1>O.CO>[Br:12][C:13]1[CH:20]=[CH:19][C:16](/[CH:17]=[N:2]/[NH:3][C:4]([NH2:6])=[O:5])=[C:15]([F:21])[CH:14]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: NC(=O)N/N=C/c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of aminourea hydrochloride (2.8 g, 25 mmol) and NaOAc (4.1 g, 49 mmol) in water (50 mL) was added dropwise a solution of 4-bromo-2-fluorobenzaldehyde (5.0 g, 25 mmol) in methanol (50 mL). The resulting solution was stirred at rt for 3 h. The solids formed were collected by filtration to obtain compound 59a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C8H7BrFN3O: 260.0 (M+H). Found: 260.1.
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].CN(C)[CH:9]=[CH:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH:2]([N:5]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(=O)C=CN(C)C
Reactant: CC(C)NN
Agent: Cl
Product: CCOC(=O)c1ccnn1C(C)C

Procedure:
The title compound was prepared in analogy to the procedure described in Step 17.3 using isopropylhydrazine hydrochloride and ethyl 4-(dimethylamino)-2-oxobut-3-enoate at 120° C. for hr. The crude product was purified by silica gel column chromatography (hexane/EtOAc 2.5-40%). tR: 4.74 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 183 [M+H]+ (LC-MS 2); Rf=0.95 (hexane/EtOAc 1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8]P(=O)(OCC)OCC)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23](/[CH:24]=[CH:8]/[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=2)=[CH:22][CH:21]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(/C=C/c2ccc(Cl)cc2)cc1

Procedure:
In an analogous manner to that described in Example 36a), the reaction of diethyl (4-nitrobenzyl)phosphonate with 4-chlorobenzaldehyde yields the (E)-1-chloro-4-[2-(4-nitrophenyl)ethenyl]-benzene as an yellow crystalline solid; MS: m/e=259 (M)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].CCN(CC)CC>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C=NO)ccc1Br
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a mixture of 4-bromo-3-methyl-benzaldehyde (372 mg, 1.87 mmol) and hydroxylamine hydrochloride (306.5 mg, 4.41 mmol) in ethanol (5 mL) at rt was added Et3N (0.15 mL). The reaction mixture was heated under reflux for 2 h, cooled to rt and concentrated under reduced pressure. The residue was dissolved in EA (10 mL), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to give 4-bromo-3-methylbenzaldehyde oxime (384 mg; yield 96%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([NH:17]C(=O)OC(C)(C)C)[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)[CH:5]=[N:4][CH:3]=1.CC1N(C2C=C(NC(=O)OC(C)(C)C)C=C(C(F)(F)F)C=2)C=CN=1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[C:9]([NH2:17])[CH:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Agent: Cc1nccn1-c1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Product: Cc1cncn1-c1cc(N)cc(C(F)(F)F)c1

Procedure:
Utilising the procedure described in Example 91d, but employing [3-(5-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester (Example 93c) in lieu of [3-(2-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-carbamic acid, 1,1-dimethylethyl ester, afforded the title compound as a colourless crystalline solid, m.p. 131-133° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.[ClH:17].C(O)C.[Cl:21]OC(C)(C)C>ClCCl>[Cl:17][C:8]1[CH:9]=[C:4]([CH2:3][CH2:2][OH:1])[CH:5]=[C:6]([Cl:21])[C:7]=1[NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Cl
Reactant: CC(C)(C)OCl
Reactant: CCOC(=O)CNc1ccc(CCO)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CNc1c(Cl)cc(CCO)cc1Cl

Procedure:
To a stirred solution of ethyl N-[4-(2-hydroxyethyl)-phenyl]aminoacetate (1.0 g) in dichloromethane (20 ml) were added concentrated hydrochloric acid (373 μl) and ethanol (3.0 ml) at room temperature, and a solution of tert-butyl hypochlorite (1.04 ml) in dichloromethane (6 ml) was added dropwise over 10 minutes period under ice-cooling with stirring. The mixture was stirred for 10 minutes, and the reaction mixture was concentrated in vacuo. A saturated aqueous sodium bicarbonate solution was added to the residue, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1) gave ethyl N-[2,6-dichloro-4-(2-hydroxyethyl)phenyl]aminoacetate (695 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1,3-butanedione (0.6 g) and diethyl oxalate (0.83 ml) in 1,2-dimethoxyethane (2 ml) was added to a stirred suspension of sodium hydride (0.44 g, 50% dispersion in mineral oil, washed with petrol 40°-60° C.) in 1,2-dimethoxyethane (5 ml) under nitrogen. The stirred mixture was heated under reflux for 1 hour, cooled and acidified with 2M hydrochloric acid (10 ml). The brown solid which formed was recrystallised from ethanol-water to give the title product (mp 93°-94° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][S:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:5][CH:4]=1.[F:19][S:20]([O:23][CH3:24])(=[O:22])=[O:21]>C(Cl)Cl>[F:19][S:20]([O-:23])(=[O:22])=[O:21].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][CH:9]2[CH:14]3[CH2:13][CH2:12][N+:11]([CH3:24])([CH2:16][CH2:15]3)[CH2:10]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(CSC2CN3CCC2CC3)cc1
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: COc1ccc(CSC2C[N+]3(C)CCC2CC3)cc1
Product: O=S(=O)([O-])F

Procedure:
The procedure described in Preparation 6-(3) was repeated, but using 756 mg of 3-(4-methoxybenzylthio)-quinuclidine and 271 μl of methyl fluorosulfonate in the presence of 5 ml of methylene chloride, to afford 1.078 g of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>ClCCl>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([CH3:1])=[N+:3]([O-:18])[CH:4]=1)#[N:7]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C#N)cn1
Solvent: ClCCl
Product: Cc1ccc(C#N)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 6-methylnicotinonitrile (4.15 g) and 3-chloroperbenzoic acid (8.3 g) in dichloromethane (200 ml) was stirred under an argon atomosphere at room temperature for 16h. The dichloromethane was evaporated under reduced pressure and the residue purified by flash column chromatography on silica (K60), using ethyl acetate and then methanol: dichloromethane (1:9 by volume) as eluting solvent to give 5-cyano-2-methylpyridine-1-oxide, mp 133.5°.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[CH:17]=[CH:18][C:19]5[N:23]=[C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6C(OC(C)(C)C)=O)[NH:21][C:20]=5[CH:36]=4)=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1.Cl.[CH3:38][O:39][C:40]([NH:42][C@@H:43]([CH:47]([CH3:49])[CH3:48])[C:44](O)=[O:45])=[O:41].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:16]4[CH:17]=[CH:18][C:19]5[N:23]=[C:22]([C@@H:24]6[CH2:28][CH2:27][CH2:26][N:25]6[C:44](=[O:45])[C@@H:43]([NH:42][C:40](=[O:41])[O:39][CH3:38])[CH:47]([CH3:49])[CH3:48])[NH:21][C:20]=5[CH:36]=4)=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(Br)ccc3-4)cc2[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)CCc3cc(Br)ccc3-4)cc2[nH]1)C(C)C
Temperature: 25 °C
Yield: 56.8 %

Procedure:
A solution of (S)-tert-butyl 2-(6-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)-pyrrolidine-1-carboxylate (582 mg, 1.1 mmol), 4M HCl solution in dioxanes (5 mL, 20 mmol) and methanol (3 mL) was stirred at room temperature for twenty minutes. The reaction was concentrated, suspended in dichloromethane, and thoroughly concentrated. This crude amine was dissolved in dimethylformamide (5 mL). To this solution were added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (281 mg, 1.6 mmol), HATU (691 mg, 1.8 mmol) and diisopropylethylamine (0.65 mL, 3.7 mmol). The reaction was stirred at room temperature for fifteen minutes, and then diluted ethyl acetate. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield Methyl (S)-1-((S)-2-(6-(7-bromo-9,10-dihydrophenanthren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (376 mg, 58%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=2[C:32](O)=[O:33])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:39]([NH2:45])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>>[O:44]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:39][NH:45][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[S:27]([CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)(=[O:29])=[O:28]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NCc1ccco1
Product: O=C(NCc1ccco1)c1ccccc1S(=O)(=O)Cc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 83.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 51 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 610 [M+H]+.