Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[C:5]([CH3:19])[O:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][CH:45]1[CH2:52][CH:51]2[N:53]([CH3:54])[CH:47]([CH2:48][CH2:49][CH2:50]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:54][N:53]1[CH:47]2[CH2:48][CH2:49][CH2:50][CH:51]1[CH2:52][CH:45]([NH:44][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:19])=[N:11][C:10]=13)=[O:18])[CH2:46]2
Reactant: Cc1noc(C)c1-c1nc2c(C(=O)O)cccc2o1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1nc2c(C(=O)NC3CC4CCCC(C3)N4C)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
A mixture of 2-(3,5-dimethylisoxazol-4-yl)benzoxazole-4-carboxylic acid (136 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg, 1.05 mmol), 1-hydroxybenzotriazole (142 mg, 1.05 mmol) and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (150 mg, 0.66 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.29 mL, 2.11 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide (99 mg, 48%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.85 (d, J=6.6 Hz, 1H), 8.22 (dd, J=7.7, 1.0 Hz, 1H), 7.69 (dd, J=8.0, 0.9 Hz, 1H), 7.47 (t, J=7.9 Hz, 1H), 4.66-4.60 (m, 1H), 4.22-4.15 (m, 2H), 2.90 (s, 3H), 2.71 (s, 3H), 2.68-2.60 (m, 2H), 2.57 (s, 3H), 2.07-1.96 (m, 3H), 1.90-1.61 (m, 3H), 1.15-1.05 (m, 2H); MS (ESI+) m/z 395 (M+H); HPLC>99% (AUC), tR=12.33 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[C:13]1(=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[NH:14]1.[K].C>CN(C)C=O>[Br:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:14]1[C:15](=[O:22])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13]1=[O:23]
Reactant: BrCCCCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCCCCCBr
Yield: 66.4 %

Procedure:
A mixture of 100.0 g of 1,10-dibromodecane and 50.0 g of 1H-isoindole-1,3(2H)-dione, potassium salt in 500 ml of N,N-dimethylformamide was stirred and heated on a steam bath for eight hours. The reaction mixture was clarified while hot with activated charcoal, then filtered. The material on the filter was washed with 100 ml of N,N-dimethylformamide. The filtrate and wash were combined and taken to dryness in vacuo. The residue was triturated with 100 ml of hexane. The insoluble product was collected, washed with 50 ml of hexane, then air dried and gave 81.0 g of 2-(10-bromodecyl)-1H-isoindole-1,3(2H)-dione.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:21][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1ccc(C#Cc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C#Cc2ccccc2)cc1OCc1ccccc1
Yield: 38.2 %

Procedure:
A stirred solution of benzyl 2-benzyloxy-4-phenylethynylbenzoate (2 g) and 1 N sodium hydroxide (5 mL) in dioxan (80 mL) is heated at reflux for 1 hour. The reaction mixture is evaporated, the residue dissolved in water (6 mL) and the solution washed twice with ethyl acetate (20 mL). The pH of the aqueous phase is adjusted to pH 1 by addition of 2 N hydrochloric acid and resulting solid is filtered and washed well with water to give 2-benzyloxy-4-phenylethynylbenzoic acid (0.6 g), m.p. 125-127° C. [Elemental analysis:- C,80.2; H,4.86%. Calculated:- C,80.5; H,4.91%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]2([OH:26])[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[O:21][CH:22]=[CH:23][CH:24]=4)=[C:14]3[C:13](=[O:25])[O:12]2)[N:4]=1.[CH3:27]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:15]2[N:16]=[CH:17][CH:18]=[C:19]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)[C:14]=2[C:13]([O:12][CH3:27])=[O:25])=[O:26])[N:4]=1
Reactant: CN(C)C=O
Reactant: COc1cc(OC)nc(C2(O)OC(=O)c3c(-c4ccco4)ccnc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1c(-c2ccco2)ccnc1C(=O)c1nc(OC)cc(OC)n1
Temperature: 25 °C
Yield: 50.7 %

Procedure:
2.1 g of 7-(4,6-dimethoxypyrimidin-2-yl)-4-(2-furyl)-7-hydroxyfuro[3,4-b]pyridin-5(7H)one was weighed out, and 50 ml of N,N-dimethylformamide and 0.82 g of potassium carbonate were added thereto. The mixture was stirred at room temperature. 0.8 g of methyl iodide was added thereto dropwise, and the mixture was stirred at room temperature overnight, then poured into water and extracted 200 ml of ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/hexane=1/3) to obtain 1.1 g (yield 50.7%) of the desired compound as brown crystals. m.p.: 135°-140° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Br:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Br:24][C:25]1[CH:30]=[C:29]([C:6]2[N:7]=[C:8]([N:10]3[C:14]4[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=4[N:12]=[CH:11]3)[S:9][C:5]=2[C:3]([OH:2])=[O:4])[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4cccc(Br)c4)c(C(=O)O)s3)c2cc1OC
Yield: 8.7 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 3-bromophenylboronic acid (30 mg, 0.15 mmol) gave 4-(3-Bromo-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (4.0 mg, 9%) as a white solid. MS 460 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11](Br)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:14]1([C:20]([C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=2)=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:25]2[CH:24]=[CH:23][C:22]([C:20]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[O:21])=[CH:27][CH:26]=2)=[N:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Br)nc(-c2ccc(C(=O)N3CCOCC3)cc2)c1N
Temperature: 110 °C
Reaction time: 64 h
Yield: 23.5 %

Procedure:
A mixture of methyl 3-amino-2,6-dibromoisonicotinate (11.4 g, 36.6 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (8.7 g, 33.3 mmol), and powdered sodium carbonate (8.12 g, 77 mmol) in a mixture of toluene (90 mL) and methanol (30 mL) was degassed and then backfilled with nitrogen twice. Tetrakis(triphenylphosphine)-palladium(0) (1.93 g, 1.67 mmol) was added and the reaction was degassed and backfilled with nitrogen. After stirred in a 110° C. oil bath for 64 hr, the reaction was cooled and then partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was separated and washed with saturated aqueous sodium bicarbonate, brine, and then dried over sodium sulfate and the solvents removed. The residue was suspended in EtOAc and the solid was collected by filtration and washed with EtOAc to give methyl 3-amino-6-bromo-2-(4-(morpholine-4-carbonyl)phenyl)-isonicotinate (3.29 gm, 24%). Flash silica gel chromatography of the filtrate (step gradient elution with hexane containing 10 to 20% EtOAc and then methylene chloride containing 1 to 4% MeOH) gave additional 4.63 g (33%) of pure product and 2.2 g of material that contained 65% of the product according to LC/MS. MS (ESI) m/z 418 and 420 (M−H). 1H NMR (CDCl3) δ ppm 7.83 (1H, s), 7.68 (2H, d, J=8.24 Hz), 7.52 (2H, d, J=7.93 Hz), 5.93 (2H, br. s.), 3.92 (3H, s), 3.78 (4H, br. s.), 3.62 (2H, br. s.), 3.46 (2H, br. s.).
Reaction SMILES: C(OC(=O)C)(=O)C.[C:8]1([CH:14]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:14]2[CH2:15][C:16](=[O:18])[O:22][C:20](=[O:21])[CH2:19]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CC(CC(=O)O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccccc2)CC(=O)O1
Yield: 89.3 %

Procedure:
To acetic anhydride (5 ml) was added 3-phenylglutaric acid (2.20 g, 10.6 mmol). The mixture was refluxed for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to obtain 1.8 g (yield 90%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6].[CH2:18](Br)[CH:19]=[CH2:20]>>[CH3:17][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:20][CH:19]=[CH2:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Reactant: C=CCBr
Product: C=CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1

Procedure:
N-[3-[3-(Dimethylamino)-1-oxo-2-propenyl]phenyl]acetamide was alkylated by the procedure of Example 3, using 7.26 g of allyl bromide, giving 13.34 g of the desired compound, mp 91°-94° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-])(=[O:3])[CH3:2].S(OC)(OC)(=O)=O.[C-:20]#[N:21].[K+]>CS(C)=O>[C:1]([NH:4][CH2:5][C:6]1[N:7]=[C:8]([C:20]#[N:21])[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1cccc[n+]1[O-]
Reactant: [C-]#N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CS(C)=O
Product: CC(=O)NCc1cccc(C#N)n1
Reaction time: 3 h
Yield: 15.2 %

Procedure:
A mixture of 2-acetylaminomethylpyridine N-oxide (1.00 g) and dimethyl sulfate (0.63 ml) was stirred for three hours. Dimethyl sulfoxide (6 ml) and potassium cyanide (392 mg) were added to the mixture and the solution was stirred for two hours at ambient temperature. Additional potassium cyanide (392 mg) was added to the mixture and which was further stirred for two hours. After the solvent was removed by concentration, the residue was mixed with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g) by eluting with a mixture of ethyl acetate and methanol (20:1) to give 6-acetylaminomethyl-2-pyridinecarbonitrile (0.16 g).
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].C1(S([Cl:23])(=O)=O)C(F)=C(F)C(F)=C(F)C=1F.S(Cl)(Cl)(=O)=O>CC(C)=O.NC1C=CC=CC=1>[ClH:23].[N:1]1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8]
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Solvent: CC(C)=O
Solvent: Nc1ccccc1
Solvent: Cc1cccc(C)n1
Product: Cl

Procedure:
Aniline 9.3 (44.6 g, 268 ummol) and 2,6-lutidine (32.8 mL, 282 mmol) were dissolved in 800 mL of acetone (the aniline only partly dissolved). An addition funnel was charged with C6F5SO2Cl (41.8 mL, 282 mmol) and the sulfonyl chloride was added over 15 minutes. During the addition, the starting material dissolved and a new precipitate (2,6-lutidine hydrochloride) formed. After 30 minutes, the 2,6-lutidine hydrochloride was removed by filtration and the filtrate concentrated under reduced pressure. The brown oily solid so produced was triturated with CH2Cl2 and the solid collected. A second batch of product was obtained by repeating the concentration, trituration, and filtration. After drying under high vacuum, 95.5 g (90%) of sulfonamide 9.4 was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:6][C@@H:7]1[C@@H:28]([N:29]2[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]2)[CH2:27][C@@:26]2([CH3:37])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:25]2[C:24](=O)[CH2:23][C@@:22]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:21])[CH2:18]C#N)[CH2:8]1.O[C@@H]1[C@@H]([N:63]2[CH2:68]COC(C)(C)C2)C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@@]2(C)[C@H]3CC[C@@H]2C(=O)CC#N)C1>>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[OH:6][C@@H:7]1[C@@H:28]([N:29]2[CH2:34][CH2:33][O:32][C:31]([CH3:36])([CH3:35])[CH2:30]2)[CH2:27][C@@:26]2([CH3:37])[C@@H:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:39])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C:17](=[O:21])[CH2:18][S:2][C:68]#[N:63])[CH2:8]1
Reactant: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@H]4[C@@H]5CC[C@H](C(=O)CC#N)[C@@]5(C)CC(=O)[C@@H]43)C[C@@H]2O)CCO1
Agent: CS(=O)(=O)O
Product: CC1(C)CN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](C(=O)CSC#N)CC[C@@H]43)C[C@@H]2O)CCO1

Procedure:
(2β,3α,5α)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-11,20-dioxopregnane-21-carbonitrile methanesulfonate (1:1) salt with the 21-cyano compound of Example 37 as starting material. δ (CDCl3) 0.66 (s,3H), 1.09 (s,3H), 1.34 (s,3H), 1.52 (s,3H), 2.81 (s,3H), 3.42 (s,2H) and 4.27 (t,J 13 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([O-:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.CCOC(C)=O.O>CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([OH:22])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)[O-])cc1
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc([C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A mixture of (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4-methoxyphenyl)propanoate (1.44 g, 4.44 mmol) and LiOH—H2O (280 mg, 6.66 mmol) in MeOH/THF (30 mL, 1:1) was stirred for 1 h at ambient temperature. EtOAc/water (30 mL/50 mL) was added and the two phases were separated. The aqueous phase was washed with EtOAc (30 mL×2) then acidified with dilute HCl to pH=5. The resulting mixture was extracted with EtOAc (50 mL×2). The organics were combined, dried over anhydrous sodium sulfate, and concentrated to afford (2S,3R)-2-(tert-butoxycarbonylamino)-3-hydroxy-3-(4-methoxyphenyl)propanoic acid (0.90 g, 65% yield) as a colorless solid.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[CH:9](=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:17]=[CH:18][C:19](=[CH2:21])[CH3:20]>C1(C)C=CC=CC=1>[CH3:20][C:19]1[CH2:21][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:16][CH2:17][CH:18]=1
Reactant: C=CC(=C)C
Reactant: O=Cc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC1=CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 11 h
Yield: 56 %

Procedure:
To a rapidly stirred solution of 70% aqueous triflic acid (2.10 g, 0.01 mol) and benzaldehyde (106.1 g, 1.0 mol) in 100 ml toluene was added isoprene (150 cm3, 1.5 mol) over 4 hrs. at 25° C. The mixture was stirred at room temperature for a further 11 hours after which the reaction mixture was quenched by the addition of Polyrad* (2 g) and solid sodium carbonate (5 g). The crude mixture was distilled under reduced pressure to give pure rosyrane (56% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[N:30]1([CH2:35][C:36](O)=[O:37])[CH:34]=[N:33][CH:32]=[N:31]1>>[N:30]1([CH2:35][C:36]([NH:1][C@@H:2]([CH2:20][O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:37])[CH:34]=[N:33][CH:32]=[N:31]1
Reactant: O=C(O)Cn1cncn1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 66 %

Procedure:
Proceeding as in Example 1, but substituting (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide and 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride, gave Compound 149, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-benzyloxy-N-(4-(4-fluorophenoxy)phenyl)propanamide (45 mg, 66%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.26 (br s, 1H), 8.84-8.78 (d, 1H), 8.48 (s, 1H) 7.96 (s, 2H), 7.63-7.59 (d, 2H), 7.32-7.28 (m, 5H), 7.23-7.19 (t, 2H), 7.04-6.98 (m, 4H), 5.03 (s, 2H), 4.76-4.69 (m, 1H), 4.54 (s, 2H), 3.69-3.67 (d, 2H). MS (EI) for C26H24FN5O4. found 490.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([Br:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[I:11]
Reactant: COC(=O)Cc1ccccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccccc1I
Temperature: 25 °C

Procedure:
A mixture of (2-iodophenyl)-acetic acid methyl ester (14.5 g, 52.5 mmol), NBS (18.7 g, 105 mmol) and AIBN (1.72 g, 10.5 mmol) in CCl4 (300 mL) is refluxed for 10 h. The mixture is cooled to RT and the precipitate filtered. The filtrate is evaporated to give the title compound.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31](OC)[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:36]C(CC)=O.C1(C)C(C)=CC=CC=1>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([CH3:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCC(C)=O
Solvent: Cc1ccccc1C
Product: CCCCc1nc2ccc(C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
tert.butyl 4'-[(2-n-butyl-6-methoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate oil, Rf value: 0.65 (Silica gel: methylethylketone/xylene=1:2)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]([Cl:21])=[CH:18][CH2:19]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:19][CH:18]=[C:17]([Cl:21])[Cl:16])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Reactant: ClCC=C(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CC=C(Cl)Cl)Cc1ccc(Cl)cc1
Yield: 66 %

Procedure:
Using 0.50 g of (4-chlorobenzyl)malononitrile, 5 ml of N,N-di-methylformamide, 0.12 g of sodium hydride (60% in oil), and 0.30 ml of 1,1,3-trichloropropene, and according to the process described in the Production Example 1, there was obtained 0.52 g of 2-(4-chlorobenzyl)-2-(3,3-dichloro-2-propenyl)malononitrile (the present compound (20)).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N([O-])=O.[Na+].[I-:18].[K+]>Cl.O>[I:18][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [I-]
Reactant: Nc1ccccc1-c1ccccc1
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Ic1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
2-Iodo-1-phenylbenzene was prepared in accordance with the procedure of Heaney and Millar, Org. Syn 40:105 (1960), was used as follows. To a solution of 2-aminobiphenyl (2.53 g, 15.0 mmol) in concentrated hydrochloric acid (3 mL) and water (15 mL) at 0° C. was added sodium nitrite (1.17 g, 17.0 mmol) in water (5 mL). The temperature was held at 0° C. throughout the addition. The resulting brown solution was stirred for 45 min at 0° C., and then poured into potassium iodide (4.9 g, 30.0 mmol) in water (50 mL). The solution was stirred overnight and then extracted with ether (4×). The combined organic layers were washed with 3N hydrochloric acid (3×10 mL) and dried over magnesium sulfate to afford 3.57 g (85%) of the desired compound as a dark purple liquid. IR (neat) 3055.7, 1578.4, 1460.0, 1426.6, 1016.7, 1004.1, 746.9 cm-1 . 1H NMR (300 MHz, CDCl3)δ 7.95 (dd, J=8.1, 1.2 Hz, 1H), 7.34 (m, 7H), 7.03 (tt, J=7.3, 1.9 Hz, 1H). 13C NMR (20 MHz, CDCl3)δ 146.3, 143.9, 139.3, 129.9, 129.1, 128.6, 128.0, 127.8, 127.5, 98.6. Calc'd for C12H9I:279.9749. Found: 279.9739.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C=Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(/C=C/c2ccccc2)cc1

Procedure:
4-Iodoanisole (58 mg, 0.25 mmol) and styrene (43 μL, 0.375 mmol) were coupled using the procedure described above, but using triethylamine (0.375 mmol, 52 μL) in place of ethyldiisopropylamine, to give 100% conversion to (E)-4-methoxystilbene by GC analysis.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=1.[OH-].[K+].Cl>C(O)C.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1

Procedure:
A solution of 4.8 g of ethyl p-{[6-(2-naphthyloxy)-hexyl]amino}benzoate and 4.8 g of potassium hydroxide in 100 ml of 95% ethanol is refluxed for 3 hours. The solution is cooled, diluted with water and acidified with concentrated hydrochloric acid. The mixture is filtered and the solid washed with ethanol with water and recrystallized from ether-methylene chloride and acetone to give crystals, mp 157°-159° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][CH2:13][C:14]([NH2:16])=[O:15])=[C:6]([C:7]#[N:8])[CH:9]=1
Reactant: NCC(N)=O
Reactant: N#Cc1cc(Br)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(Br)ccc1NCC(N)=O
Temperature: 100 °C
Yield: 77.3 %

Procedure:
16.3 g (81.5 mmol) 5-bromo-2-fluorobenzonitrile, 9.2 g (83.1 mmol) glycinamide hydrochloride and 23.6 g (170.8 mmol) K2CO3 were suspended in 40 ml DMSO and heated at 100° C. for 3 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 16.0 g (77%) 2-(4-bromo-2-cyano-phenylamino)acetamide was obtained. ESI-MS [m/z]: 254, 256 [M+H]+