Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([O:15][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].[Cs+].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33]>C(C#N)(C)=O.C(Cl)Cl>[C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([O:15][CH2:29][CH2:30][O:31][CH2:32][CH3:33])[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)[Si](Oc1cccc2[nH]c(C3=CCCC3)cc12)(C(C)C)C(C)C
Reactant: CCOCCBr
Agent: CC(=O)C#N
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Product: CCOCCOc1cccc2[nH]c(C3=CCCC3)cc12
Temperature: 60 °C
Yield: 73.7 %

Procedure:
To 500 mg (1.41 mmol) of 2-cyclopent-1-enyl-4-triisopropylsilyloxy-1H-indole (14d step 1) in 5 mL AcCN was added 255 mg (1.68 mmol, 1.2 eq) of CsF and 479 μL (4.23 mmol, 3 eq) 2-bromoethylethyl ether. The reaction was heated at 60° C. overnight then cooled to rt, diluted with CH2Cl2 and filtered through celite and concentrated. The residue was partitioned between ether and H2O, the ether layer was then washed with aqueous NaCl solution, dried (MgSO4), and concentrated under vacuum to yield 282 mg (74%) of 2-cyclopent-1-enyl-4-(2-ethoxy-ethoxy)-1H-indole.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(OCC)=O)C.[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.O>C1(C)C=CC=CC=1.C1COCC1>[Cl:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: O=Cc1cccc([N+](=O)[O-])c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)/C=C/c1cccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon, 98 mg (2.46 mmol, 60% pure) of sodium hydride were suspended in 2 ml of toluene and 2 ml of THF, and the suspension was cooled to 0° C. 0.6 ml (2.57 mmol) of tert-butyl (diethoxyphosphoryl)acetate was then slowly added dropwise, and the mixture was stirred at 0° C. for 30 min. 415 mg (2.24 mmol) of 2-chloro-3-nitrobenzaldehyde were then added to the reaction mixture, and the reaction mixture was then warmed to room temperature. The mixture was stirred at room temperature for 2 hours, and 5 ml of water were then added. After removal of the organic phase, the aqueous phase was extracted three more times with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). This gave 429 mg (1.51 mmol, 59% of theory) of the title compound.
Reaction SMILES: NC1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1.CI.C(=O)([O-])[O-].[K+].[K+].[CH3:29][N:30]([CH3:33])[CH:31]=O>O>[CH3:29][N:30]([CH3:33])[C:31]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=3[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cccc2cc(-c3ccc(N)cc3)oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc2cc(-c3ccc(N(C)C)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.6 g of methyl 2-(4-aminophenyl)benzofuran-7-carboxylate, 1.52 ml of methyl iodide, 6.72 g of potassium carbonate and 25 ml of dimethylformamide is stirred at room temperature for 1 hour. 2.2 ml of methyl iodide are added to the mixture and the mixture is stirred for 2 hours. The reaction mixture is poured into water and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:4) to give 2.0 g of methyl 2-(4-dimethylaminophenyl)benzofuran-7-carboxylate as orange needles.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20.0 g amount of 7-(3-(trifluoromethyl)-phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxylic acid, ethyl ester (U.S. Pat. No. 4,178,449, Example 16) stirred in 100 ml of glacial acetic acid and cooled in a water bath is added portionwise 10.0 g of sodium cyanoborohydride under nitrogen. The mixture is stirred at room temperature for 3 hours. Evaporation of the mixture in vacuo gives an oil which solidifies on treatment with water. This solid is collected by filtration and is then stirred with a saturated solution of sodium bicarbonate, then is filtered, washed with water and dried in vacuo to give a white solid. Recrystallization from isopropyl alcohol gives 18.2 g of the desired product, mp 108-110° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][CH:3]=1.[CH:10]1([C:16]2[CH:23]=[CH:22][C:19](C=O)=[CH:18][CH:17]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH2:24](O)C>>[CH2:19]1[CH2:18][CH2:17][CH:16]([C:10]([C:15]2[CH:24]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N+:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O-:9])[CH2:23][CH2:22]1
Reactant: CCO
Reactant: ONc1ccc(Cl)cc1
Reactant: O=Cc1ccc(C2CCCCC2)cc1
Product: [O-][N+](=C(c1ccccc1)C1CCCCC1)c1ccc(Cl)cc1

Procedure:
p-Chlorophenylhydroxylamine (0.05 moles) was dissolved in warm 95% ethanol (40 cc) and was treated with p-cyclohexylbenzaldehyde (0.05 moles) with vigorous stirring. The solid which formed was collected, washed with 95% ethanol, and was recrystallized from ethanol to give α-p-cyclohexylphenyl-N-p-chlorophenylnitrone.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=O)[CH2:5][CH:4]([CH3:9])[S:3]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.C([SiH](CC)CC)C>ClCCl>[Br:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:6]1[CH2:7][CH:2]([CH3:1])[S:3][CH:4]([CH3:9])[CH2:5]1
Reactant: CCOC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CC1CC(=O)CC(C)S1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(C3CC(C)SC(C)C3)c[nH]c12
Temperature: 0 °C
Yield: 26.3 %

Procedure:
2,6-Dimethyltetrahydro-4H-thiopyran-4-one (0.293 g, 2.03 mmol) was dissolved in dichloromethane (35 mL) in an oven dried flask containing 3 Å molecular sieves and stirred under argon at 0° C. TMS-OTf (0.451 g, 2.03 mmol, 0.36 mL) was added slowly to the mixture over 10 min. Ethyl 5-bromo-1H-indole-7-carboxylate (0.293 g, 2.031 mmol) was dissolved in DCM (10 mL) and added to the reaction via syringe pump over 2 hours, after which it was stirred for 3 hours between 0 and 10° C. The reaction was cooled to 0° C. and triethylsilane (0.353 g, 0.485 mL, 3.04 mmol) was then added all at once and the reaction was stirred at room temperature overnight. The reaction was then quenched with a saturated sodium bicarbonate solution, filtered, then extracted with DCM. The combined organics were washed with water. The combined aqueous layers were back-extracted with DCM. The combined organics were washed with brine, dried with MgSO4, and concentrated. The crude compound was purified on Combiflash silica column with 0-30% EA/DCM to give 0.212 g (26%) of the title compound.
Reaction SMILES: C[N:2]([CH3:16])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.N[C:18]1[C:22]([C:23]#[N:24])=C[NH:20][N:19]=1>C(O)(=O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[N:20]3[N:19]=[CH:18][C:22]([C:23]#[N:24])=[C:16]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: CN(C)C=CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccc([N+](=O)[O-])c3)ccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 24.4 g of 3-dimethylamino-3'-nitroacrylophenone, 13.0 g of 3-aminopyrazole-4-carbonitrile and 120 ml of glacial acetic acid was heated at reflux for 7 hours, then was stirred at room temperature for 16 hours. The precipitate was collected, triturated with saturated aqueous sodium bicarbonate, filtered and washed with water. The solid was then triturated with acetonitrile, filtered and dried and gave the desired product, mp 244°-246° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(NC(C)C)(C)C>C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#CC(C)(C)O)cc2)cc1

Procedure:
A stirred mixture of compound 68 (15.00 g, 0.039 mol), 2-methylbut-3-yn-2-ol (7.15 g, 0.085 mol), copper(I) iodide (0.34 g, 1.80 mmol), tetrakis(triphenylphosphine)palladium(0) (2.89 g, 2.50 mmol) and diisopropylamine (150 ml) was heated under reflux in a dry nitrogen atmosphere for 24 h. The resultant mass was dissolved in THF and filtered over hyflo filter aid to remove inorganic materials. Volatile materials were removed in vacuo and the brown solid was recrystallised from ethanol to give a white, fluffy solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].C1COCC1.O.[OH-].[Na+:40]>CCO>[CH3:1][C:2]1[S:3][C:4]([CH3:32])=[C:5]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=2)[C:6]=1[C:7]([NH:9][C@H:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-:18])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[Na+:40]
Reactant: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)O)cc2)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1sc(C)c(C(=O)N[C@@H](C)c2ccc(C(=O)[O-])cc2)c1Cc1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 4-{(1S)-1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]ethyl}benzoic acid from Example 12 (1.70 g, 3.68 mmol) in a mixture of EtOH (50 mL), THF (15 mL) and water (15 mL) was added NaOH (1N in water, 3.68 mL, 3.68 mmol). After 10 min. the solution was concentrated to dryness and the residue was dried under high vacuum to afford the desired product as an off-white solid. MS (−APCI): m/z 460 (M−23)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:11](=O)(O)[O-].[Na+]>CO>[CH3:11][O:9][C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)=[O:10]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccnc(Cl)c1
Reaction time: 0.67 h

Procedure:
2-Chloropyridine-4-carboxylic acid (15.5 g, 98 mmol) was suspended in methanol (175 ml) and anhydrous hydrogen chloride gas was slowly bubbled through the reaction mixture while cooling in a methanol/water (20/80) dry ice bath. Bubbling was continued for 40 min. during which time the suspension cleared to a partial solution. Ice bath was removed and the reaction mixture was heated to reflux under anhydrous conditions for 30 min. to give a clear yellow solution. The solution was cooled in an ice bath and saturated sodium bicarbonate was slowly added with stirring till the pH was neutral. The organics were removed in vacuo and the product was extracted into ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-chloropyridine-4-carboxylic acid methyl ester as a brown liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=[C:12]([C:18]([F:21])([F:20])[F:19])[N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9].[F:22][C:23]1[CH:24]=[C:25]([CH:35]([CH3:39])[C:36](O)=[O:37])[CH:26]=[CH:27][C:28]=1[CH2:29][NH:30][S:31]([CH3:34])(=[O:33])=[O:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>O1CCCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[C:15]([CH2:16][NH:17][C:36](=[O:37])[CH:35]([C:25]3[CH:26]=[CH:27][C:28]([CH2:29][NH:30][S:31]([CH3:34])(=[O:32])=[O:33])=[C:23]([F:22])[CH:24]=3)[CH3:39])=[CH:14][CH:13]=[C:12]([C:18]([F:20])([F:21])[F:19])[N:11]=2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1
Reactant: CC(C(=O)O)c1ccc(CNS(C)(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(=O)NCc1ccc(C(F)(F)F)nc1-c1ccc(F)c(Cl)c1)c1ccc(CNS(C)(=O)=O)c(F)c1
Reaction time: 48 h

Procedure:
To a stirred solution of (2-(3-chloro-4-fluorophenyl)-6-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.104 g, 3.632 mmol) and 2-(3-fluoro-4-(methylsulfonamidomethyl)phenyl)propanoic acid (1 g, 3.632 mmol) in tetrahydrofuran (28 mL) was added 1-hydroxybenzotriazolhydrate (0.49 mL, 3.632 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.166 g, 3.632 mmol) and N-ethyldiisopropylamine (1.852 mL, 10.896 mmol) and the reaction mixture was allowed to stir for 48 h. The reaction mixture was concentrated under reduced pressure and the solid obtained was purified by column chromatography (eluent:ethyl acetate/cyclohexane 2:1) to afford a white solid (example 16) (605 mg, 30%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30](O)=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:38])=[O:31])[C:18]([C:33]([F:35])([F:34])[F:36])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
2-(2-(2-(2-((3-(4-Methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (I68) (75.0 mg, 169 μmol) was dissolved in DMF (1 mL) then HATU (129 mg, 339 μmol), DIPEA (57 uL, 339 μmol) and ammonium chloride (181 mg, 3.39 mmol) were added. The resulting mixture was stirred at room temperature overnight then the volatiles were evaporated under reduced pressure. The residue was diluted with ethyl acetate and washed with 10% NaHCO3, the layers were separated and the organic layer was dried (MgSO4) then evaporated under reduced pressure to give a cream solid. The cream solid was adsorbed onto silica and chromatographed on silica gel (0-10% MeOH/DCM) to give the title compound (17) (23.3 mg, 28%) as a cream solid; 1H NMR (400 MHz, CD3CN) δ 8.57 (s, 1H), 8.34 (s, 1H), 7.58 (s, 1H), 7.30-7.16 (m, 5H), 7.09 (d, J=8.0 Hz, 1H), 6.71 (dd, J=8.2, 1.9 Hz, 1H), 3.61 (s, 2H), 3.27 (t, J=4.9 Hz, 4H), 3.19-3.03 (m, 4H), 2.92 (bs, 4H), 2.91 (s, 3H). LCMS Method C: rt 4.43 min; m/z 499.7.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C:13]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:27]([O:34][C:35]([NH:37][C:38](=NC(OCC1C=CC=CC=1)=O)SC)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)(=O)C>[C:28]1([CH2:27][O:34][C:35]([NH:37][C:38]2[NH:1][C:2]3[CH:3]=[C:4]([C:9]4[CH:10]=[CH:11][C:12]5[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14][C:13]=5[CH:26]=4)[CH:5]=[CH:6][C:7]=3[N:8]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc4nc(NC(=O)OCc5ccccc5)[nH]c4c3)cc2C1
Temperature: 60 °C
Yield: 45.1 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.0 g, 5.6 mmol) in acetic acid (20 mL) was added 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea (2.4 g, 6.7 mmol) and the resulting mixture was heated (60° C.). After 12 h the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was then washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. Column chromatography on silica (0 to 50% ethyl acetate/hexanes) provided 1,1-dimethylethyl 7-[2-({[(phenylmethyl)oxy]carbonyl}amino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.3 g, 45% yield) as a brown solid. MS (EI) for C29H30N4O5: 515 (MH+).
Reaction SMILES: [CH:1]([OH:5])=[C:2]([OH:4])[CH3:3].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>C[Si](N[Si](C)(C)C)(C)C>[Si:7]([O:4][CH:2]([CH2:1][O:5][Si:7]([CH3:9])([CH3:8])[CH3:6])[CH3:3])([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(O)=CO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(CO[Si](C)(C)C)O[Si](C)(C)C

Procedure:
1,2-Propenediol (58.8 g, 0.77 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.2 mL trimethylsilyl chloride. A small volume of HMDS (ca. 10 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (170 mL) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50°-70° C. Heating was continued at 100° C. (1.5 h), 120° C. (1.0 h), and 140° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 147 g of colorless oil, bp 70°-72° C./10 mm. 1H NMR (CDCl3): 3.83 (m; 1H), 3.50 and 3.38 (AB pattern with additional coupling, 2H), 1.15 (d, J=7 Hz, 3H), 0.15 (partially resolved singlets, 18H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:21][C:22]#[N:23].[Na+]>C(O)(=O)C.O>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:16][CH2:17][N:18]([C:22]([NH2:23])=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2CCNCC2)cc1CC1CCCC1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C2CCN(C(N)=O)CC2)cc1CC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(3-cyclopentylmethyl-4-methoxyphenyl)piperidine (1.8 mmol, 0.500 g) in acetic acid (5 mL) was added a solution of sodium cyanate (10.8 mmol, 0.702 g) in water (15 mL) dropwise over 20 minutes at room temperature. The resulting solution was stirred at room temperature overnight, after which the acetic acid was removed in vacuo. The residue was partitioned between EtOAc (200 mL) and H2O (200 mL). The aqueous phase was extracted with EtOAc (1×200 mL), the combined organics dried (Na2SO4), concentrated in vacuo and purified by flash chromatography (SiO2 ; EtOAc) to give the title compound as a white solid, mp=168°-169° C. (0.5 mmol, 1.054 g, 27%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[O-:5])[CH3:2].[C:13](#[N:16])[CH:14]=[CH2:15].[H-].[Na+].C(O)(=O)C>C(O)C>[C:13]([CH2:14][CH2:15][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])(=[O:5])[O:3][CH2:1][CH3:2])#[N:16]
Reactant: CCOC(OCC)P([O-])OCC
Reactant: C=CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(OCC)P(=O)(CCC#N)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The starting material can be prepared as follows: A solution of 20 g of ethyl(diethoxymethyl)phosphonite (Aust. J. Chem. 33, 292 (1980)) and 5 g of acrylonitrile in 25 ml of ethanol is added to a stirred mixture of 1 g of sodium hydride (50% dispersion in oil) in 25 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 26 ml of water, and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 2-cyanoethyl(diethoxymethyl)phosphinate, b.p. 114° C./0.01 mbar, 31P=+40.8 ppm (CDCl3).
Reaction SMILES: [N+]([C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=C(C)C=1)([O-])=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.BrN1C(=O)CCC1=O>O>[CH2:7]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:6][CH2:5][CH3:4]
Reactant: CCCCOc1ccc([N+](=O)[O-])cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCCCOCCCC
Reaction time: 8 h

Procedure:
To a stirred and gently refluxing mixture of 256 parts of butyl (5-nitro-o-tolyl) ether, 1 part of benzoyl peroxide and 4800 parts of anhydrous carbon tetrachloride is added, over a one-day period, a mixture of 213.6 parts of N-bromosuccinimide and 1 part of benzoyl peroxide. Upon completion, stirring at gentle reflux is continued overnight. The reaction mixture is cooled and water is added. The organic layer is separated, washed with water, dried, filtered and evaporated. The oily residue is crystallized on standing overnight in 2-propanol, yielding 189.7 parts of (α-bromo-5-nitroo-tolyl) butyl ether; mp. 64° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9].[CH3:17]O>>[CH3:5][NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:8]([O:10][CH3:17])=[O:9]
Reactant: CO
Reactant: CNC(C(=O)O)c1ccccc1
Solvent: O=S(Cl)Cl
Product: CNC(C(=O)OC)c1ccccc1
Reaction time: 2 h

Procedure:
6.63 mL of thionyl chloride are slowly added to a solution of 1.5 g of 2-methylamino-2-phenylacetic acid in 100 mL of methanol. The mixture is heterogenous and becomes limpid after two hours stirring. The mixture is stirred for 48 h at rt then the solvent is evaporated to dryness. The crude product is diluted with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phases are washed with water then brine, and dried over magnesium sulfate, filtered and evaporated to provide the desired product, which is used as such for the next step.