Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:23])C)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].BrBr.[OH-].[Na+].Cl.S(S([O-])=O)([O-])(=O)=[O:30].[Na+].[Na+]>O1CCOCC1.O>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(C(C)=O)cc3)cc2)CC1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(c2ccc(-c3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(4′-acetylbiphenyl-4-yl)cyclopropanecarboxylic acid ethyl ester (10.1 g, 33 mmol) in dioxane (200 mL) at ˜10° C. was added a solution of bromine (26.4 g, 165 mmol), sodium hydroxide (22.4 g, 561 mmol) in water (150 mL). The solution was stirred at room temperature for 30 minutes, poured into water (500 mL) and acidified with dilute hydrochloric acid. Sodium metabisulfite was added until the brown bromine color dissipated. The product was filtered and dried in a vacuum over overnight at 40° C. to yield 10 g of 4′-(1-(ethoxycarbonyl)cyclopropyl)biphenyl-4-carboxylic acid.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][N:7]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2.CN(C)CCN(C)C.[CH:29](N1CCCCC1)=[O:30].Cl>C(OCC)C>[CH3:6][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:29]=[O:30])[C:13]=2[S:14][C:15]2[C:20]1=[CH:19][CH:18]=[CH:17][CH:16]=2
Reactant: CN1c2ccccc2Sc2ccccc21
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CN1c2ccccc2Sc2c(C=O)cccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
21.7 ml of tert-butyllithium solution (1.4M in pentane) were slowly added dropwise under argon at -78° to a solution of 5.0 g (23.4 mmol) of 10-methylphenothiazine in 10 ml of absolute diethyl ether and 7 ml of freshly distilled N,N,N',N'-tetramethylethylenediamine. The reaction mixture was subsequently brought slowly to room temperature, stirred for 18 hours, then cooled to 0° and thereupon treated with 3.90 ml (35.1 mmol) of N-formylpiperidine. The reaction mixture was stirred at room temperature for 2 hours and then poured into 50 g of ice, 50 ml of 0.1N aqueous hydrochloric acid solution and 1.50 ml of diethyl ether. The aqueous phase was extracted twice with 100 ml of diethyl ether and the combined organic fractions were dried over magnesium sulphate and concentrated. The residue was chromatographed on 500 g of silica gel with ethyl acetate/hexane (1:3), whereafter, after recrystallization from ethyl acetate/hexane, 4.20 g (74.4%) of 10-methyl-phenothiazine-4-carbaldehyde were obtained as a yellow solid of m.p. 103°.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11](/[CH:38]=[CH:39]/[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1>CS(C)=O.[H-].[Na+]>[NH2:7][C:8]1[C:13]2[C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:25])=[C:19]([O:36][CH3:37])[CH:18]=3)=[CH:15][S:16][C:12]=2[C:11]([CH:38]2[CH2:2][CH:39]2[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:10][N:9]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)/C=C/c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1c1cnc(N)c2c(-c3ccc(NC(=O)c4cc5ccccc5n4C)c(OC)c3)csc12
Temperature: 25 °C
Yield: 30.2 %

Procedure:
Trimethylsulfoxonium iodide (45.1 mg, 0.205 mmol) in anhydrous methyl sulfoxide (4 mL) and 60% sodium hydride in mineral oil (16.4 mg, 0.411 mmol) was stirred for 5 minutes at room temperature and treated with a mixture of ethyl (2E)-3-[4-amino-3-(3-methoxy-4-{[(1-methyl-1H-indol-2-yl)carbonyl]amino}phenyl)thieno[3,2-c]pyridin-7-yl]acrylate (108 mg, 0.205 mmol) in methyl sulfoxide (2 mL) was added. After 4 hours the mixture was cooled to room temperature and quenched with saturated ammonium chloride solution (7 mL). The aqueous layer was extracted with dichloromethane (3×10 mL), dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The crude product was purified via HPLC preparative to give the title compound as a white solid (33.6 mg 0.062 mmol): LCMS (Conditions a): MH+=541 Rt=4.20 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1H), 7.99 (1H), 7.69 (2H), 7.58 (2H), 7.35 (2H), 7.18 (1H), 7.15 (1H), 7.06 (1H), 5.49 (1H), 4.18 (2H), 4.04 (3H), 3.91 (3H), 2.45 (1H), 1.86 (1H), 1.56 (1H), 1.47 (1H), 1.26 (3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:11][C:12]1[N:13]=[CH:14][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:16]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 120 °C
Yield: 48.4 %

Procedure:
4-fluoronitrobenzene (32.3 g; 0.229 mol) and 4-methyl-1H-imidazole (25 g; 0.3 mol) are mixed at r.t., to this stirred mixture K2CO3 (44 g; 0.3 mol) is added. The reaction mixture is then heated at 120° C. overnight, then cooled at r.t. and poured in water (2 L), the resulting suspension is filtered and washed with water. The obtained solid is dried at 60° C. and recrystallized from ethyl acetate (600 mL), to provide the title compound as a yellow solid (22.5 g; 48.3%). The regioisomer, 4-(5-methyl-1H-imidazol-1yl)nitrobenzene remains in the crystallization mother liquor along with a certain amount of the titled product (TLC: hexane/AcOEt 3:2). C10H9N3O2, MW 203.2.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[N:8]=[C:9]([NH2:14])[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:5][CH:6]=1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH2:13][C:11]1[N:10]=[C:9]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[N:12]=1
Reactant: Nc1nc(N)nc(-c2ccccc2)n1
Reactant: O=C(O)c1cccnc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Nc1nc(NC(=O)c2cccnc2)nc(-c2ccccc2)n1

Procedure:
5.7 g of benzoguanamine and 4.0 g of nicotinic acid are dissolved in 300 ml of pyridine, and this solution is stirred with 5.0 g of phosphoryl chloride at room temperature. After continuing agitation at 60° C for 2 hours, the pyridine is removed by evaporation to dryness under vacuum. The residue is washed with water and fractionated and recrystallized from a mixed solution of methanol and dioxane, to yield 2-amino-4-nicotinamido-6-phenyl-s-triazine [mononicotinoylbenzoguanamine], melting point, 240° - 242° C in a yield of 2.8 g, and 2,4-bis(nicotinamido)-6-phenyl-s-triazine [dinicotinoylbenzoguanamine], melting point, 131° - 133° C in a yield of 0.7 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[NH:7][C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])([O-:3])=[O:2].[O:23]1CCC[CH2:24]1.[H-].[Na+].C(N1C=CN=C1)(N1C=CN=C1)=O>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[N:12]([CH2:13][CH2:14][CH3:15])[C:24]2=[O:23])[CH:20]=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: CCCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3.0 g of 2-(m-nitroanilino)-N-propylbenzamide and 50 ml of tetrahydrofuran were added 1.1 g of 50 % sodium hydride and 4.9 g of 1,1' -carbonyldiimidazole. The mixture was stirred for one hour at room temperature and then refluxed for 5 hours. After the reaction was finished, the solvent was distilled off from the resulting mixture under reduced pressure, and to the residue obtained was added water to yield a precipitate. This product was recrystallized from methanol to yield 2.6 g of 1-(m-nitrophenyl)-3 -propylquinazoline-2,4(1H, 3H)-dione as colorless prisms, melting at 162°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[CH2:16][CH2:17][C:18](OC)=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[CH:13][C:12]=2[CH2:16][CH2:17][CH2:18][OH:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)CCc1cnoc1-c1ccc(OC)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2oncc2CCCO)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of methyl 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propionate (1.70 g) in tetrahydrofuran (20 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 15 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3,4-dimethoxyphenyl)-4-isoxazolyl]propan-1-ol (1.26 g, yield 82%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 55–56° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:41])[C:29]([N:31]([CH3:40])[CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:25])([F:26])[F:27])[CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:28](=[O:41])[C:29]([N:31]([CH3:40])[CH2:32][C:33]([OH:35])=[O:34])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)OC(C)(C)C)C(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC(=O)O)C(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3cccc(OC(F)(F)F)c3)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.3 %

Procedure:
To an ice-cooled solution of tert-butyl 2-[(2-{1-benzyl-5-[3-(trifluoromethoxy)phenyl]-1H-indol-3-yl}-2-oxoacetyl)(methyl)amino]acetate (5.17 g, 9.13 mmol) in methylene chloride (60 mL) was added trifluoroacetic acid (30 mL, 390 mmol). The reaction mixture was stirred for 1.5 hours at room temperature and concentrated. The residue was treated with diethyl ether and the mixture was concentrated to the precipitation point. The solid was purified by HPLC using 70% acetonitrile/0.1% formic acid in water as the mobile phase. The acetonitrile was evaporated, and the aqueous phase was extracted with ethyl acetate and washed with water and brine. The organic phase was evaporated to dryness and the residue was dried for 15 hours at 91° C. to give the title compound as a light pink solid (2.81 g, 60%), mp 178–179° C. Mass spectrum (−ESI, [M−H]−) m/z 509; 1HNMR (500 MHz, DMSO-d6): δ12.8–13.2 (br, 1H), 8.45 (m, 1H), 8.35 (d, 1H, J=8.4 Hz), 7.7–7.8 (m, 3H), 7.55–7.65 (m, 2H), 7.4–7.45 (m, 2H), 7.25–7.35 (m, 5H), 5.6 (d, 2H, J=3.5 Hz), 4.15 (d, 2H, J=21.0 Hz), and 3.0 ppm (dd, 3H, J=22.0 Hz and 0.78 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:14])[CH:3]=1.S(Cl)([Cl:17])=O>ClCCCl>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([F:14])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClCCCl
Product: Nc1cc(F)c(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
Prepared analogously to example 53a from 4-amino-5-nitro-2-fluoro-benzoic acid and thionyl chloride in 1,2-dichloroethane.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH:24]=[C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CN1C(=O)CCC1.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH:24]=[C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:22]=[C:21]([NH:42][CH:39]([CH3:41])[CH3:40])[N:20]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)N
Reactant: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5cncc(C6CC6)n5)cc34)nc(S(C)(=O)=O)n2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5cncc(C6CC6)n5)cc34)nc(NC(C)C)n2)cc1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(6-cyclopropylpyrazin-2-yl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole (26 mg, 0.049 mmol) and isopropylamine (0.4 ml, 4.66 mmol) in NMP (0.5 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 1 h. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic layer was washed with water, dried, filtered and concentrated to give the crude compound, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 507.0 (M+1).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[CH:9]1)(OC(C)(C)C)=O.[CH3:52][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[CH3:1][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:39])[CH3:40])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[CH:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3cn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 295 mg (0.43 mmol) of 2-[3-(N-BOC-indol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Example 23, in 10 mL of DMF at 0° C. is added 690 μL (0.69 mmol, 1.6 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 10 min, then 53 μL (0.86 mmol, 2.0 equiv) of methyl iodide is added. The reaction mixture is stirred 2 h at RT and then heated to 50° C. for 14 h, then quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL EtOAc and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. The crude material is then resubjected to the same conditions as stated above to ensure complete alkylation. The crude material is then dissolved in 10 mL of 4N HCl in dioxane and the reaction mixture is stirred 6 h at RT. The reaction mixture is diluted with 40 mL of EtOAc and extracted with NaHCO3 (1×30 mL) and H2O (1×30 mL). The organic layer is dried (MgSO4) and the solvents removed in vacuo. The resulting crude oil is purified via reverse phase MPLC using a C-18 column and 65% acetonitrile/35% H2O as eluent followed by lyophilization to afford 51 mg of 2-[3-(N-methyl-indol-3-ylmethyl)-3-methyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide as a white amorphous solid. 1H NMR (DMSO-d6, 300 MHz) δ7.61-6.88 (m, 18H), 4.86 (m,1H), 4.28 (m, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.71 (dd, 2H, J=14.9, 35.4), 1.25 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 615 (MH+), 614 (M+).
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[O:10])[CH:4]=[CH:3]1.[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:24])[CH3:23])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28]C1C(=O)C=CCC1(C)C)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[C:20]([O:21][SiH:22]([CH3:23])[CH3:24])=[C:19]([Br:25])[C:18]([O:26][CH3:27])=[CH:17][C:16]=1[CH2:28][C@@H:6]1[C:5](=[O:10])[CH:4]=[CH:3][C@@H:2]([CH3:1])[C:7]1([CH3:9])[CH3:8])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1C=CC(=O)CC1(C)C
Reactant: COc1cc(CC2C(=O)C=CCC2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br
Product: COc1cc(C[C@@H]2C(=O)C=C[C@@H](C)C2(C)C)c(C(C)(C)C)c(O[SiH](C)C)c1Br

Procedure:
This compound was prepared from 4,5,5-trimethylcyclohex-2-en-1-one (10) (169 mg, 1.22 mmol) in the manner previously described for benzylated enone 11, affording 0.337 g (59%) of the less polar trans diastereomer as a colorless, oily solid, along with 22 mg (4%) of the more polar cis diastereomer as a colorless, oily solid, separable by flash column chromatography. The relative stereochemistry of each respective diastereomer was confirmed by nOe NMR experiments. 1H NMR (400 MHz, CDCl3) δ 0.21 and 0.23 [2s, 2×3H, Si(CH3)2 ], 0.98 [s, 9H, SiC(CH3)3 ], 0.90 and 1.10 (2s, 2×3H, geminal-CH3 's), 1.11 (d, 3H, CHCH3), 2.45 (dd, 1H), 2.53 (ddd, 1H), 2.72 and 2.97 (d of ABq, 2H, benzylic-H's), 3.81 (s, 3H, OCH3), 5.87 (dd, 1H, 2-H), 6.55 (dd, 1H, 3-H), 6.64 (s, 1H, Ar--H), 6.93 ppm (s, 1H, Ar--H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C([S:22][C@@H:23]1[CH2:28][O:27][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:25][CH2:24]1)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([S:22][C@@H:23]1[CH2:24][O:25][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: CC(=O)S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and trans-5-(acetylthio)-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane to obtain the desired compound having a melting point of 73 to 75° C. in a yield of 70%.
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[Cl:12][CH:13]([C:20]([O:22][CH3:23])=[O:21])[CH2:14][S:15][CH2:16][C:17]([NH2:19])=O.Cl>N1C=CC=CC=1>[Cl:12][CH:13]([C:20]([O:22][CH3:23])=[O:21])[CH2:14][S:15][CH2:16][C:17]#[N:19]
Reactant: COC(=O)C(Cl)CSCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)C(Cl)CSCC#N
Reaction time: 4 h
Yield: 81.7 %

Procedure:
Tosyl chloride (18.82 g) was added in portions to a stirred solution of 5-chloro-5-methoxycarbonyl-3-thiapentanamide (19 g), in dry pyridine (95 ml). Heat was evolved during the addition. The mixture was stirred for 4 hours, stood overnight, and poured into 4M hydrochloric acid (400 ml) and extracted with dichloromethane. The combined extracts were washed with 4M hydrochloric acid (×3) and saturated brine, dried (magnesium sulphate) and evaporated to obtain the title compound as a dark red oil (14.2 g) 1H n.m.r. δ (CDCl3) 3.28 (2H,d, J=7Hz, CH2CH), 3.45 (2H, s, CH2CN), 3.83 (3H,s,CO2Me), 4.54 (1H,t, J=7Hz, CH2CH).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#[N:12].[C:13]([O:17][C:18](=[O:26])[N:19]([CH2:23][CH2:24]Cl)[CH2:20][CH2:21]Cl)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[C:13]([O:17][C:18]([N:19]1[CH2:23][CH2:24][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])([C:11]#[N:12])[CH2:21][CH2:20]1)=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#CCc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccc2Cl)CC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 30.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.28 g, 45 mmol) was suspended in DMF (20 mL) and cooled in an ice bath under a nitrogen atmosphere. (2-Chloro-phenyl)-acetonitrile (1.77 g, 11.7 mmol) in DMF (5 mL) was added slowly, and the mixture stirred for 2 hours. Bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (3.3 g, 11.1 mmol) in DMF (5 mL) was then added and the mixture heated to 75° C. for 6 hours. The solvent was removed by evaporation under vacuum and the residue dissolved in ethyl acetate (50 mL), washed with water, then brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by silica chromatography eluting with a mixture of ethyl acetate and hexane. The fractions containing the desired products were combined and the solvent removed by evaporation to give the title compound as an orange gum (1.1 g). LCMS m/z 321.0 [M+H]+. R.T.=4.76 min (Analytical Method 4).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH2:5][C:6]#[CH:7].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C1COCC1.CCCCCC>[Si:9]([O:8][CH2:3][CH2:4][CH2:5][C:6]#[CH:7])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C#CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a suspension of 18.0 g (749 mmol, 1.05 equiv.) of sodium hydride in 500 mL of THF at 0° C. was added a solution of 60.0 g (713 mmol, 1.00 equiv.) of 4-pentyne-1-ol in 150 mL of THF. When the addition was complete the reaction was allowed to warm to room temperature over one hour. To this mixture was added 113 g (749 mmol, 1.05 equiv.) of t-butyldimethylsilyl chloride in 150 mL of THF. The reaction was allowed to stir for 16 hours at room temperature then diluted with 1200 mL of hexane. The organic layer was washed with 500 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting liquid was distilled at 39°-42° C. at 0.05 mm Hg to yield 135 g (96%) of 1-t-butyldimethylsilyloxy-4-pentyne