Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10])[C:3](=[O:6])[CH2:4][Cl:5].C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[O:9]1[CH2:10][CH2:12][O:11][CH:8]1[CH2:7][N:2]([CH3:1])[C:3](=[O:6])[CH2:4][Cl:5]
Reactant: COC(CN(C)C(=O)CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Solvent: CCOCC
Product: CN(CC1OCCO1)C(=O)CCl
Temperature: 25 °C

Procedure:
N-Methyl-N-(2,2-dimethoxyethyl)-2-chloroacetamide (19.5 grams; 0.10 mole), ethylene glycol (6.82 grams; 0.11 mole) and 10 drops of a solution of one gram of p-toluenesulfonic acid in 100 ml of diethyl ether were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distillation head and condenser. The mixture was stirred and heated to about 100° C. to 110° C. Byproduct methanol was distilled off. When no further methanol was evolved, the mixture was cooled to room temperature, sodium carbonate (2 grams) was added and the slurry was stirred for a period of about 1 hour. The slurry was then filtered and the filtrate fractionally distilled under reduced pressure. The desired product N-(1,3-dioxolan-2-ylmethyl)-N-methyl-2-chloroacetamide was obtained as a fraction boiling at 124° C. at 0.30 mm Hg and at 119° C. at 0.15 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 19-hydroxyandrost-4-ene-3,17-dione in acetic anhydride and pyridine is allowed to stand overnight after which the reaction mixture is poured into ice water. The resulting solid is collected, dried and recrystallized from hexane to give 19-acetoxyandrost-4-ene-3,17-dione.
Reaction SMILES: [C:1]([CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][CH:6]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[C:5]1=[O:32])#[N:2].[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C.Cl>CN1CCCC1=O>[C:15]1([C:8]2[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:4]([CH2:3][C:1]3[NH:35][N:34]=[N:33][N:2]=3)[C:5](=[O:32])[CH:6]([N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[N:7]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#CCN1C(=O)C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(c2ccccc2)c2ccccc2N1Cc1nnn[nH]1
Temperature: 145 °C
Yield: 91.1 %

Procedure:
To a solution of (3RS)-1-cyanomethyl-1,3-dihydro-5-phenyl-3-phthalimido-2H-1,4-benzodiazepin-2-one (100.0 g) and sodium azide (46.4 g) in 1-methyl-2-pyrrolidone (1.74 l) was added triethylamine hydrochloride (49.1 g) under stirring. The mixture was heated on an oil-bath at 145° C. and stirred for 4 hours. The reaction mixture was poured into 5% hydrochloric acid (4.8 l) under cooling and stirring. The resultant precipitate was collected by filtration, washed with water several times and dried in vacuo at 50° C. for 5 hours to afford (3RS)-1,3-dihydro-5-phenyl-3-phthalimido-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (100.39 g).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([Mg]Cl)[CH:16]=[CH2:17]>O1CCCC1>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:8])[CH2:17][CH:16]=[CH2:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: C=CC[Mg]Cl
Solvent: C1CCOC1
Product: C=CCC(O)(c1ccccc1)c1ccccc1
Reaction time: 16 h

Procedure:
To 29 g of benzophenone in 150 mL of tetrahydrofuran (THF) at 0° C. was added 88 mL of 2M allyl magnesium chloride. After 16 hrs, the starting material was completely consumed as indicated by thin layer chromatography (TLC). To the reaction mixture was added 1 mL of methanol to quench the excess Grinard reagent. The THF was distilled in vacuo and the residue was shaken with dilute aqueous hydrochloric acid and chloroform. The layers were separated and the aqueous phase was extracted with chloroform. The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give 37 g of 1,1-diphenyl-3-buten-1-ol which is characterized by:
Reaction SMILES: [CH:1]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[C:32]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:26]5[C:21]4=[CH:22][CH:23]=[CH:24][CH:25]=5)[CH:15]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].O.Cl[C:39]([CH3:42])([CH3:41])[CH3:40]>>[C:39]([C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([N:20]4[C:21]5[CH:22]=[CH:23][C:24]([C:5]([CH3:6])([CH3:13])[CH3:4])=[CH:25][C:26]=5[C:27]5[C:32]4=[CH:31][CH:30]=[C:29]([C:26]([CH3:27])([CH3:21])[CH3:25])[CH:28]=5)[CH:15]=3)[C:13]3[C:5]([C:6]=2[CH:7]=1)=[CH:4][C:3]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:2][CH:1]=3)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)(C)Cl
Reactant: c1cc(-n2c3ccccc3c3ccccc32)cc(-n2c3ccccc3c3ccccc32)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc2c(c1)c1cc(C(C)(C)C)ccc1n2-c1cccc(-n2c3ccc(C(C)(C)C)cc3c3cc(C(C)(C)C)ccc32)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1,3-di(carbazol-9-yl)benzene (1.0 g, 2.45 mmol) in 2-chloro-2-methylpropane (10.0 ml) was added aluminum trichloride (0.32 g, 2.40 mmol) at room temperature under nitrogen atmosphere and stirring. After the addition of AlCl3, insoluble 1,3-di(carbazol-9-yl)benzene disappeared within minutes. The green solid appeared after 5 minutes of reacting at room temperature. The reaction was carried out at room temperature for another 10 minutes. TLC showed that the reaction was finished. After which, water (20.0 ml) was added and the green solid became white. The solid product was collected with filtration and washed with methanol. The product was purified by recrystallization from acetone/THF/methanol to yield a white solid in the amount of 1.23 g (79.4%).
Reaction SMILES: [C:1]([N:9]1[C@@H:13]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12](=[O:18])OC1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH2:28])[CH3:27])=[CH:22][CH:21]=1.Cl>C(OCC)(=O)C>[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:12](=[O:18])[C@H:13]([C:14]([CH3:15])([CH3:16])[CH3:17])[NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:27])=[CH:22][CH:21]=1
Reactant: CC(C)(C)[C@H]1C(=O)OC(=O)N1C(=O)c1ccccc1
Reactant: Cc1ccc([C@H](C)N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1ccc([C@H](C)NC(=O)[C@@H](NC(=O)c2ccccc2)C(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
(S)-3-Benzoyl-4-tert-butyl-2,5-oxazolidinedione (N-benzoyl-L-tert-leucine-NCA)(100 mg, 0.38 mmol) was dissolved in ethyl acetate (2.0 mL), followed by the addition of a solution of (S)-1-(p-tolyl)ethylamine (52 mg, 0.38 mmol) in ethyl acetate (2.0 mL) at 0° C. The resulting mixture was stirred for 30 minutes. The reaction mixture was poured into 1 N hydrochloric acid (10 mL), followed by extraction with ethyl acetate (10 mL). The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and a saturated aqueous solution of sodium chloride (10 mL), and was then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to afford the title compound (66 mg, 49%) as white crystals.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:16])[F:15])[CH2:8][OH:9])[CH2:3][CH2:2]1>ClCCl.C(OCC)(=O)C.O=[Mn]=O>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=2[O:13][CH:14]([F:15])[F:16])[CH:8]=[O:9])[CH2:2][CH2:3]1
Reactant: OCc1ccc(OC(F)F)c(OC2CC2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=Cc1ccc(OC(F)F)c(OC2CC2)c1
Yield: 75.9 %

Procedure:
To a solution of the 3-Cyclopropyloxy-4-difluoromethoxybenzyl alcohol from Step 5 (41 g, 179 mmol) in dichloromethane (1.2 μL) was added MnO2 (220 g, 2.15 mol) in four portions over 2 days. When TLC indicated the reaction was complete, the mixture was diluted with ethyl acetate and filtered through Celite® (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.), washing extensively with a succession of ethyl acetate, dichloromethane, EtOH and toluene. The combined filtrates were concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 3:1 to 7:3) provided the 3-Cyclopropyloxy-4-difluoromethoxybenzaldehyde compound (31 g).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([B:23]2[O:27]C(C)(C)C(C)(C)[O:24]2)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:56]C(C)(C)C)(=[O:55])[C@@H:52]([CH3:54])O>C1COCC1>[B:23]([C:18]1[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[O:22][C@@H:52]([CH3:54])[C:51]([OH:56])=[O:55])([OH:24])[OH:27]
Reactant: CC1(C)OB(c2cc(Cl)ccc2O)OC1(C)C
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O

Procedure:
DIAD (3 ml) was added to a mixture of the product from step b) (3.51 g), triphenyl phosphine (3.98 g), tert-butyl (R)-(+) lactate (2.02 g) and THF (80 ml) at 0° C. overnight. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (7:3) to give the sub-title compound (4 g). The intermediate obtained was dissolved in acetone and 1M HCl (15 ml) was added, stirred for 20 min, then concentrated in vacuo. Redissolved in dichloromethane (10 ml) and added TFA (5 ml). Stirred for 2 h, then added water (1 ml), stirred for 1 h. The reaction mixture was then diluted (water) and made alkaline by adding dilute NaOH. The organic layer was separated and discarded. The aqueous phase was acidified with concentrated HCl to pH 1, then washed with dichloromethane (×2). These organic extracts were dried (MgSO4) then concentrated in vacuo to give the sub-title compound. Yield 1.4 g
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([F:32])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C(=O)([O-])[O-].[K+].[K+].[CH3:39][C:40]1[CH:44]=[CH:43][NH:42][N:41]=1.CO>CN1CCCC1=O.[Cu]>[F:32][C:5]1[CH:4]=[N:3][C:2]([N:42]2[CH:43]=[CH:44][C:40]([CH3:39])=[N:41]2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])[C:6]=12
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(Br)ncc(F)c12
Reactant: Cc1cc[nH]n1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)n1
Temperature: 160 °C
Yield: 13.8 %

Procedure:
A mixture of 1-(7-bromo-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (50 mg, 0.1 mmol), potassium carbonate (13 mg, 0.1 mmol), copper (6.0 mg, 0.1 mmol) and 3-methylpyrazole (32 uL, 0.4 mmol) in N-methylpyrrolidinone (0.5 mL) was heated at 160° C. for 6 h. MeOH (3 mL) was added and the solution was filtered through Celite. Solvent was removed in vacuum and residue was dissolved in DMF and purified using reverse phase prep HPLC to afford 1-(4-fluoro-7-(3-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (6.9 mg) as a white solid; 1HNMR (500 MHz, CDCl3) δ 8.46 (d, J=2 Hz, 1H), 8.19 (s, 1H), 8.93 (d, J=2.0 Hz, 1H), 7.55-7.50 (m, 5H), 6.25 (d, J=2.0 Hz, 1H), 3.78 (m, 2H), 3.56 (m, 2H), 3.35 (m, 2H), 3.25 (m, 2H), 2.36 (s, 3H). LCMS: m/e 501 (M+H)+, ret time 2.34 min (method 2) and 1-(4-fluoro-7-(5-methyl-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (13.7 mg); 1HNMR (500 MHz, CDCl3) δ 8.25 (m, 1H), 8.08 (bs, 1H), 7.65 (m, 1H), 7.60 (m, 5H), 6.27 (m, 1H), 3.87 (m, 2H), 3.66 (m, 2H), 3.46 (m, 2H), 3.36 (m, 2H), 2.83 (s, 3H). LCMS: m/e 501 (M+H)+, ret time 2.34 min (method 2).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([NH2:16]=O)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)(=O)C.[ClH:28]>C(OCC)(=O)C.[Pd]>[ClH:28].[C:18]1([C:11]2([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([NH2+][O-])C1(c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)C1(c2ccccc2)CCNCC1
Temperature: 5 °C

Procedure:
Combine 1-benzyl-4-phenylpiperidine-4-carboxylic acid amide N-oxide (529 g, 1700 mmol), 10% palladium-on-carbon (25 g), and acetic acid (5 L) in an autoclave. Flush the autoclave with nitrogen and then charge with 255 psi of hydrogen. Stir while recharging the autoclave with hydrogen as required to maintain the pressure above 100 psi. When hydrogen consumption ceases, flush the autoclave with nitrogen remove the catalyst by filtration. Evaporate the filtrate invacuo to give a residue. Dissolve the residue in ethyl acetate (5 L), acidify by the addition of 12M aqueous hydrochloric acid solution (150 mL), and heat to reflux for 15 minutes. Cool the mixture to 5° C. to give solid. Collect the solid by filtration, rinse with ethyl acetate, and air dry to give the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:7][C:6]=1[O:12][C:13]([F:14])([F:16])[F:15])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCN(CC)C(=O)c1ccc(O)cc1OC(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a stirring solution of N,N-diethyl-4-hydroxy-2-(trifluormethoxy)benzamide (1876 mg, 6.8 mmol) and diisopropylethylamine (1747 mg, 13.5 mmol) in dry DMF (60 mL) was added chloro(1,1-dimethylethyl)dimethylsilane (1123 mg, 7.5 mmol). The reaction was stirred for 16 h and then quenched with 1M HCl. The reaction was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, 0–40% EtOAc in hexanes) to give 1941 mg of the desired product as a colorless oil. MS (ESI) 392 (M+H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[CH:17]=[O:18].S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O>CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[Cl:7][C:8]1[CH2:14][CH:13]2[N:15]([CH3:16])[CH:10]([CH2:11][CH2:12]2)[C:9]=1[C:17]1[O:18][CH:31]=[N:30][CH:29]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CN1C2CCC1C(C=O)=C(Cl)C2
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CN1C2CCC1C(c1cnco1)=C(Cl)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-2-formyl-8-methyl-8-azabicyclo[3.2.1]oct-2-ene oxalate (0.55 g, 2 mmol) in 20 ml methanol powdered potassium carbonate (1.5 g) and tosylmethylisocyanide (0.4 g, 2 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. Upon evaporation in vacuo water (30 ml) was added to the residue and the water solution extracted with methylenechloride (3×20 ml). The combined methylenechloride extracts were dried and evaporated in vacuo. The residue was dissolved in ethanol, and the title compound precipitated with a 1M oxalic acid ether solution. The compound was filtered and dried. M.p. 69°-71° C. decomposes.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[CH3:2].[H-].[Na+].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][N:26]=[C:25](Cl)[N:24]=1>CN(C=O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[CH:27][N:26]=[C:25]([NH:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:6]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)[CH2:13][CH2:12]2)[N:24]=1
Reactant: N#Cc1cnc(Cl)nc1N
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(Nc3ncc(C#N)c(N)n3)CC2)ccc1OC
Temperature: 25 °C
Yield: 34 %

Procedure:
To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h 4-amino-2-chloro-pyrimidine-5-carbonitrile (15.5 mg, 0.10 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 19.7 mg (34%) of the title compound. MS (ISP): 383.4 [M+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.[I-].[Na+]>[CH2:12]([O:1][N:2]1[C:6](=[O:7])[C:5]2[C:4](=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:3]1=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 261.5 %

Procedure:
3.0 g (18 mmol) of N-hydroxysuccinimide was dissolved in 30 mL of N,N-dimethylformamide, mixed with 0.81 g (20 mmol) of 60 wt % sodium hydride (dispersed in mineral oil) under cooling with ice and stirred at room temperature for 30 minutes. After the stirring, 2.8 mL (20 mmol) of bromohexane and 35 mg (0.23 mmol) of sodium iodide were added dropwise successively under cooling with ice, and the reaction mixture was stirred at 70° C. for 20 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water, and the solid precipitated in the reaction mixture was collected by filtration and dried to give 5.82 g of the desired product as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:9]([C:10]([O:12]C)=[O:11])[C:8]([OH:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:15][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:9]=1[C:10]([OH:12])=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Reactant: OCc1ccccc1
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1

Procedure:
The title compound was prepared in analogy to example 2.10 from methyl 5-(methanesulfonyl)salicylate and benzylalcohol. MS (m/e): 305.3 (M−H, 100%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].OO.C([OH:16])C>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][N+:4]([O-:16])=[CH:3][C:2]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cnccn1
Reactant: CCO
Agent: OO
Solvent: CC(=O)O
Product: CCOC(=O)c1c[n+]([O-])ccn1

Procedure:
Compound 26--Ethyl pyrazine carboxylate-4-oxide 3.4 g hydrogen peroxide (30%) was added in three portions over a period of 1 hour to a solution of 3.06 g of ethyl pyrazine carboxylate (prepared as above) in 15 ml of glacial acetic acid at 65° C. After stirring for 16 hours another 3.4 g hydrogen peroxide were added and the solution was stirred for 48 additional hours. The volume of the mixture was reduced, 30 ml of ethanol were added and the solution was filtered. The liquid was evaporated and the residue purified on silica gel with toluene/ethyl acetate to give 0.5 g (14.80) of white ethyl pyrazinecarboxylate-4-oxide; m.pt. 128° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](Br)=[CH2:17])[C:11](=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:25]2[CH:26]=[CH:27][C:22]([CH:20]=[O:21])=[CH:23][CH:24]=2)=[CH2:17])[C:11](=[O:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Br)Cn1ccc(OCc2ccccc2)cc1=O
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(C=O)cc1

Procedure:
To 6.17 g (19.3 mmol) 4-benzyloxy-1-(2-bromo-allyl)-1H-pyridin-2-one (preparation 9a), 3.76 g (25.1 mmol) 4-formylphenylboronic acid and 1.56 g (1.35 mmol) tetrakis-triphenyl-phosphanepalladium in 150 ml 1,4-1,4-dioxanee and 45 mL MeOH is added 19.3 mL (38.5 mmol) 2M aqueous Na2CO3-solution under a nitrogen atmosphere. The reaction mixture is evacuated three times and flushed with nitrogen. The mixture is refluxed overnight under a nitrogen atmosphere and is diluted with water. The phases are separated and the aqueous phase is extracted with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. To the residue is added MeOH/acetonitrile, the mixture is filtered and purified via reverse HPLC chromatography (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:8][CH2:9][CH3:10].C(N(CC)CC)C>C(Cl)Cl>[CH2:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH2:8][CH2:9][CH3:10]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCNS(=O)(=O)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(S(=O)(=O)NCCCC)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 65.4 %

Procedure:
A solution of 20.91 g (0.20 mol) of methacryloyl chloride in 80 ml of methylene chloride was added to a solution of 45.86 g (0.20 mol) of N-butyl-4-hydroxybenzenesulfonamide, 20.24 g (0.20 mol) of triethylamine and 320 ml of methylene chloride and cooled to 0° C. over a period of approximately 20 minutes. The mixture was then stirred for another 1.5 hours with cooling, washed three times with water, dried over magnesium sulfate and concentrated in vacuo in a warm bath. The resultant oil (Note 1) was cooled and crystallized to an oily solid. Removal of residual solvent with high vacuum caused this material to completely solidify. This solid was recrystallized from 600 ml of cyclohexane with filtering. Collection of the white solid and drying at room temperature in vacuo gave 38.9 g of N-butyl-4-methacryloyloxybenzenesulfonamide; m.p.=59° to 60° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]=1.Br[CH2:16][C:17]1[CH:36]=[CH:35][C:20]2/[C:21](=[C:31](/[CH3:34])\[C:32]#[N:33])/[C:22]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:23]=3[O:24][CH2:25][C:19]=2[CH:18]=1>>[F:30][C:27]1[CH:28]=[CH:29][C:22]2=[C:23]([CH:26]=1)[O:24][CH2:25][C:19]1[CH:18]=[C:17]([CH2:16][N:10]3[C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[N:7]=[C:6]3[C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:36]=[CH:35][C:20]=1/[C:21]/2=[C:31](/[CH3:34])\[C:32]#[N:33]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1coc(-c2nc3ccccc3[nH]2)c1
Product: C/C(C#N)=C1/c2ccc(Cn3c(-c4ccco4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 94.4 %

Procedure:
Using commercially available 2-(furan-2-yl)-1H-benzo[d]imidazole (62 mg, 0.34 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (146 mg, 94%) was obtained.