Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[C:18]([F:24])[CH:17]=1>CN(C=O)C>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]2)=[C:18]([F:24])[CH:17]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccc(Br)cc2F)c2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In an oven dried 20 mL scintillation vial, indole-3-carboxylic acid (500 mg, 3.10 mmol) was massed. The vial was charged with a stir bar and DMF (10 mL), and then capped under an atmosphere of nitrogen. The solution was cooled to 0° C., followed by addition of NaH (60% dispersion in mineral oil, 375 mg, 9.38 mmol). The reaction was allowed to stir for 5 min. 4-Bromo-2-fluorobenzyl bromide (1.00 g, 3.73 mmol) was added in one portion, and the reaction was allowed to stir 15 min at 0° C. then warmed to 25° C. over 30 min. Reaction was monitored by LCMS, and upon completion was quenched cautiously with H2O. The reaction mixture was diluted with dichloromethane (20 mL) and the organic layer was acidified to pH 1 with 1M HCl. The aqueous layer was extracted with dichloromethane (3×20 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with hexanes/ethyl acetate (0 to 100%) to afford 1-(4-bromo-2-fluorobenzyl)-1H-indole-3-carboxylic acid as a solid (LCMS: RT=0.795 min, (M+H)+ m/z=348).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][C:15]=2[F:23])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([O:7]C)=[O:6]>CCO>[F:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][C:15]=2[F:23])=[C:4]([CH:9]=[CH:10][C:11]=1[F:12])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F
Solvent: CCO
Product: O=C(O)c1ccc(F)c(F)c1Nc1ccc(CCO)cc1F
Yield: 93 %

Procedure:
Methyl 3,4-difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]benzoate was deprotected using EtOH/1 M NaOH as above to afford 3,4-difluoro-2-[2-fluoro-4-(2-hydroxyethyl)anilino]benzoic acid as a crystalline cream solid (93%); m.p. (EtOAc/hexane) 196–200° C. 1H NMR [400 MHz, (CD3)2SO] δ 13.67 (v br s, 1 H), 9.28 (br s, 1 H), 7.80 (ddd, J=8.4, 6.1, 1.8 Hz, 1 H), 7.13–6.93 (m, 4 H), 4.65 (br s, 1H), 3.63–3.55 (br m, 2 H), 2.69 (t, J=6.8 Hz, 2 H). Anal. calcd. for C15H12F3NO3: C, 57.9; H, 3.9; N, 4.5. Found C, 58.3; H, 4.1; N, 4.7.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([Sn](C)(C)C)=[CH:14][CH:13]=1.O>CN(C)C=O.[Pd](Cl)Cl.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>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3](=[O:4])[CH3:2])=[CH:14][CH:13]=1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: O=C(CBr)c1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccccc1-c1ccc(C)cc1
Temperature: 150 °C
Yield: 71.2 %

Procedure:
A vigorously stirred solution of 13.25 g (66 mmol) of 2-bromoacetophenone and 22.8 g (89 mmol) of 4-methylphenyltrimethylstannane in 190 mL of dimethylformamide under a nitrogen atmosphere was treated with 8.64 g (12 mmol) of bis(triphenylphosphine) palladium(II) chloride and the resulting mixture heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into water (1000 mL) and the resultant suspension extracted with ethyl ether. The combined extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by preparative high pressure liquid chromatography on silica gel, eluting with hexane/ethyl acetate (10:1), to give 9.8 g (47 mmol, 71%) of the product as an oil. EI-MS: calculated for C15H14O 210: found 210 (M+). 1H NMR (200 MHz, CDCl3): 1.98 (s, 3H), 2.37 (s, 3H), 7.20 (s, 4H), 7.3-7.5 (m, 4H).
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][Si](C)(C)C.[CH3:13][C:14]([CH3:23])([CH2:19][N+:20]([O-:22])=[O:21])[CH2:15][C:16](=O)[CH3:17]>ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH3:13][C:14]([CH3:23])([CH2:19][N+:20]([O-:22])=[O:21])[CH2:15][C:16]1([CH3:17])[O:6][CH2:5][CH2:4][O:3]1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: CC(=O)CC(C)(C)C[N+](=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C[N+](=O)[O-])CC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A stirred solution of 1,2-bis(trimethylsilyloxy)ethane (26.5 g, 128 mmol) in dichloromethane (50 mL) was cooled in a dry ice/isopropanol bath, and trimethylsilyl trifluoromethanesulfonate (2.2 g, 1.0 mmol) was added, followed by the dichloromethane solution of 4,4-dimethyl-5-nitropentan-2-one (50 mL, 19.0 g, 119 mmol) from the previous step. After 30 minutes, the cooling bath was removed and the solution was allowed to warm to room temperature. The solution was filtered through a plug of potassium carbonate and concentrated under reduced pressure to provide 2-(2,2-dimethyl-3-nitropropyl)-2-methyl-[1,3]dioxolane (23.5 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[NH2:15]
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)C(F)F)cc1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Nc1ccc(OC(F)(F)C(F)F)cc1F
Reaction time: 2 h
Yield: 85 %

Procedure:
0.20 Gram of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)nitrobenzene, 0.03 g of platinum dioxide and 5 ml of ethyl acetate were added to a reactor, and the atmosphere in the reactor was replaced by a hydrogen stream with stirring. Stirring was then continued at room temperature for 2 hours while introducing a hydrogen gas. Thereater, the reaction solution was filtered off, and the filtrate was concentrated to obtain 0.15 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)aniline.
Reaction SMILES: Cl[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[O:3]1.[H][H].Cl>[Pt].C1(C)C(C)=CC=CC=1>[C:4]1([C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][O:3]1)=[O:5]
Reactant: [H][H]
Reactant: O=C1OC(Cl)c2ccccc21
Agent: [Pt]
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=C1OCc2ccccc21

Procedure:
842.5 parts of 3-chlorophthalide and 750 parts of xylene were heated in a stirring vessel with 25.3 parts of a catalyst composed of 5% Pt on charcoal, at 85° C., and 160 liters of hydrogen were fed in hourly. After a reaction time of 13 hours, hydrogen chloride ceased to evolve. The reaction mixture was separated from the catalyst and worked up by distillation. 549 parts of phthalide were obtained, corresponding to 81.9% of the theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:36]I)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:36][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH3:34])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OCC)C1
Reactant: Oc1cnc(-c2ccc(Cl)cc2)nc1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccccc2OCC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 2-(4-chloro-phenyl)-pyrimidin-5-ol (Preparation 27) and 1-(2-ethoxy-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 16) to afford the racemate as a white solid (238 mg, 83.9%)
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])=[O:4].C([O:17][C@@H:18]1[C@@H:23]([O:24]C(=O)C)[C@@H:22]([O:28]C(=O)C)[C@@H:21]([CH2:32][O:33]C(=O)C)[O:20][C@@H:19]1Br)(=O)C>C(OCC)(=O)C>[O:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[C@@H:19]1[O:20][C@H:21]([CH2:32][OH:33])[C@H:22]([OH:28])[C@H:23]([OH:24])[C@H:18]1[OH:17]
Reactant: COC(=O)CCCCCCCCO
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
8-Methoxycarbonyl-1-octanol (21.4 g, 0.115 mole) and dried mercuric cyanide (30.3 g, 0.119 mole) were dissolved in a 1:1 mixture of dry distilled benzene-nitromethane (850 ml). The solution was stirred and 200 ml of solvent was distilled. Mixed solvent (200 ml) was added and calcium sulfate (40 g) was added followed by 2,3,4,6-tetra-O-acetyl-α-D-galactosyl bromide (38.7 g, 0.094 mole). The mixture was stirred at room temperature for 36 h and then heated at 70° for 2 h. After cooling, the solution was filtered and the filtrate evaporated in vacuo to give a yellow syrup. This syrup was dissolved in distilled ethyl acetate (500 ml) and the solution was washed with an aqueous solution (10% w/w, 500 ml) of sodium iodide. The organic phase was then washed successively with a saturated solution of sodium thiosulphate (200 ml) and H2O (2 × 250 ml). The organic phase was dried over sodium sulphate and then evaporated in vacuo after filtration. This syrup (~50 g) after drying under high vacuum overnight was dissolved in dry distilled methanol (200 ml) and to this solution, 200 ml of methanolic sodium methoxide (150 mg of sodium) was added. After stirring at room temperature for 24 h, acid resin (prewashed a few times in methanol) was added and stirred until the pH was neutral. After filtration, the solution was evaporated and the waxy residue dissolved at room temperature in 100 ml of H2O. This solution was extracted with ether (2 × 40 ml) and then placed in the fridge. Upon standing, crystallization occurred. The white crystals were filtered and dried. Weight 13.5 g (41%), mp 104°-105°, [α]D25 - 13.4° (c 1, 95% ethanol).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=O)=[CH:6][CH:5]=1.Cl.[NH2:31][OH:32].C(=O)([O-])O.[Na+]>>[OH:32]/[N:31]=[C:12](/[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)\[CH2:11][C@H:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([N:2]([CH3:29])[CH3:1])=[O:28])=[CH:5][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C(=O)N(C)C)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C(=O)N(C)C)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from N,N-dimethyl-4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzamide and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=402.4 ([M+H]+).
Reaction SMILES: [C-:1]#[N:2].[Na+].F[C:5]1[CH:6]=[CH:7][C:8]2[C:9](=[O:21])[C:10]3[C:15]([O:16][C:17]=2[CH:18]=1)=[CH:14][C:13]([O:19][CH3:20])=[CH:12][CH:11]=3>CN(C)C=O>[CH3:20][O:19][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:21])[C:8]1[CH:7]=[CH:6][C:5]([C:1]#[N:2])=[CH:18][C:17]=1[O:16]2
Reactant: [C-]#N
Reactant: COc1ccc2c(=O)c3ccc(F)cc3oc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)c3ccc(C#N)cc3oc2c1
Temperature: 100 °C

Procedure:
A mixture of finely ground sodium cyanide (1.3 g, 26.5 mmol) and 3-fluoro-6-methoxy-xanthen-9-one (2.3 g, 9.42 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. for 4 hours. Sodium cyanide (0.7 g, 14.3 mmol) was added and heating continued an additional hour. The mixture was allowed to cool to room temperature, then poured into ice water (˜150 mL). The product was collected by filtration, washed with water and air dried to give Compound 5i, 1.42 g (60%). MS: m/z 251.9 (MH+). 1H NMR(CDCl3): δ 3.96 (s, 3 H), 6.91 (d, 1 H, J=2.3 Hz), 7.00 (dof d, 1 H, J=2.3 & 8.9 Hz), 7.61 (d of d, 1 H, J=1 & 8.1 Hz), 7.79 (d, 1 H, J=1 Hz), 8.24 (d, 1 H, J=8.9 Hz) and 8.42 (d, 1 H, J=8.1 Hz).
Reaction SMILES: N#N.[N:3]([C@H:6]1[C@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7]1)=[N+:4]=[N-:5].C1COCC1.[F-:34].C([N+](CCCC)(CCCC)CCCC)CCC>>[N:3]([C@H:6]1[C@@H:10]([F:34])[CH2:9][N:8]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:7]1)=[N+:4]=[N-:5]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2N=[N+]=[N-])cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@H](N=[N+]=[N-])C1

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar, a reflux condenser, and under inert atmosphere (N2), a solution of trans-tert-butyl 3-azido-4-(tosyloxy)pyrrolidine-1-carboxylate (438 mg, 1.15 mmol) in 1M tetra-n-butyl-ammonium fluoride solution in THF (7.00 mL, 7.00 mmol) was stirred at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was extracted with CH2Cl2, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by FC (Hept/EA, 9:1→7:3) to afford cis-tert-butyl 3-azido-4-fluoropyrrolidine-1-carboxylate as a colorless oil. TLC: rf (Hept/EA, 7:3)=0.33. LC-MS-conditions 08: tR=0.81 min; [M-CH3+H]+=216.15.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][CH2:16][C:17]([OH:19])=O)[CH3:14].[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:21]>C(Cl)Cl>[CH2:20]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17](=[O:19])[CH2:16][O:15][CH2:13][CH3:14])[CH3:21]
Reactant: CCNCc1ccccc1
Reactant: CCOCC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCOCC(=O)N(CC)Cc1ccccc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A suspension of 1,1′-carbonyldiimidazole (4.68 g, 28.86 mmol) in dry DCM (15 mL) was added portion-wise over 15 min to a solution of ethoxyacetic acid (2.09 mL, 22.12 mmol) in DCM (30 mL) under nitrogen at room temperature. The resulting solution was stirred under nitrogen for 1 h and then treated with a solution of N-ethylbenzylamine (6.60 mL, 44.37 mol) in dry dichloromethane (30 mL) drop-wise over 15 min. The resultant solution was stirred under nitrogen at room temperature for 18 h and then partitioned with aqueous HCl (2M, 2×75 mL) and the combined organic layer dried (MgSO4), filtered and reduced in vacuo to give an oil. Purification by SPE (silica, 2×50 g cartridges), eluting with cyclohexane:EtOAc gradient 15:1 to 1:1 afforded the title compound as a pale yellow oil (4.36 g).
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[O:15])C(O)=O)=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1.[OH-].[Na+].Cl>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:15])=[O:1])=[C:6]([N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: OO
Reactant: O=C(O)C(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A 30% hydrogen peroxide solution (4.95 mL, 0.04 mol) was added dropwise to a solution of 4-bromo-2-nitrophenylpyruvic acid (0.04 mol) and sodium hydroxide (5.3 g 0.1 mol) in water (175 mL) stirring at 0° C. The reaction solution was stirred for 1 h at 5° C. and then acidified with dilute HCl. The yellow precipitate was filtered and the crude product recrystallized from hexane and ethyl acetate to yield 8.4 g (75%) as a light beige solid; 1H-NMR (DMSO-d6): δ12.67 (br s, 1H), 8.28 (d, J=2.0 Hz), 7.97 (dd, 1H, J=9.0 Hz, 2.0 Hz), 7.55 (d, 1H, J=8.0 Hz 4.00 (s, 3H). MS (−ve) m/z: 259 (M−H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[C:16]([C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]=1)#[N:17]>C1COCC1>[C:13]([CH:14]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH:19]1[CH2:18][C:16]#[N:17])#[N:15]
Reactant: COc1ccc2c(c1)CCC=C2C#N
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)CCC(CC#N)C2C#N
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 74.2 %

Procedure:
To a solution of 1.05 mL (7.5 mmol) of diisopropylamine in 10 mL of THF at -78° C., under a nitrogen atmosphere, was added n-butyllithium (2.2 mL of a 2.5 M solution in THF, 5.5 mmol) and the resultant solution was stirred at -78° C. for 40 min. To the stirred solution was added, dropwise over a 25 minute period, a solution of 274 μL (5.25 mmol) of acetonitrile in 5 mL of THF. The solution was stirred for 20 min at -78° C. and then a solution of 926 mg (5 mmol) of 1-cyano-6-methoxy-3,4-dihydronaphthalene (the product of Step 2 of Example 1) in 5 mL of THF was added via syringe pump over a 20 min period. The reaction mixture then allowed to warm to ambient temperature and was was stirred at ambient temperature for 1 h and then the reaction was quenched by pouring the reaction mixture into saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with 25% ethyl acetate in hexane to give 840 mg (74% yield) of the title compound as a 1:1 mixture of the cis and trans isomers; MS DCI-NH3M/Z: 244 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Nc1ccn(Cc2ccccc2)n1
Product: Cc1cn(-c2ccc(Nc3ccn(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-benzyl-1H-pyrazol-3-ylamine. The title compound was obtained as a yellow solid (Yield=74%). MS ISP (m/e): 355.2 (100) [(M+H)+].
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.Cl>O1CCOCC1.CCCCCC>[N:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][N:7]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:6]2=3)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: BrCCCCCCN1CCCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1COCCO1
Solvent: CCCCCC
Product: O=C1Nc2cccnc2N(CCCCCCN2CCCCC2)c2ccccc21
Temperature: 70 °C

Procedure:
To a suspension of 33.2 g (0.157 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 875 ml of anhydrous dioxan, 173 ml (approx. 0.45 mol) of a 2.6 molar solution of n-butyl-lithium in n-hexane was added dropwise at ambient temperature and the resulting mixture was then stirred for another hour at the same temperature. It was then heated to 70° C. and at a reaction temperature of not more than 75° C. 83.0 g (0.034 mol) of 1-bromo6-(1-piperidinyl)hexane were added dropwise, then to complete the reaction the mixture was stirred for a further 4 hours at 80° C. After cooling, the solvent was distilled off in a water jet vacuum, the residue was adjusted to pH 7 with dilute aqueous hydrochloric acid and the mixture was then filtered. The filtrate was made alkaline with concentrated aqueous potassium hydroxide solution and extracted exhaustively with dichloromethane. The dichloromethane extracts were dried over sodium sulphate and then evaporated down and the residue remaining was digested with 100 ml of boiling diethyl ether and filtered while hot. The residue remaining after the ether had been removed was purified by chromatography on silica gel (Macherey-Nagel, 0.2-0.5 mm) using dichloromethane/methanol/cyclohexane/ethyl acetate/conc. ammonia 59/7.5/7.5/25/1 (v/v/v/v/v) as eluant. By evaporating the desired fractions and subsequently recrystallising from acetonitrile, a colourless crystalline product with a m.p. of 131° to 132° C. was obtained in a yield of 11.29 g (19% of theory). The hydrochloride melted at 223° C. (ethanol).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3.[H][H]>C(O)(=O)C.[Pd]>[O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]2=[N:5][CH:4]=[C:3]1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: CCOC(=O)c1cnc2c3ccccc3ccn2c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2n(c1=O)CCc1ccccc1-2

Procedure:
A mixture of ethyl 4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (2.68 g., 0.010 mole) in acetic acid (200 ml.) containing 10% palladium on carbon (1.0 g.) was shaken with hydrogen at an initial pressure of about 4 kg. cm.-2 until the theoretical pressure drop was reached (3.3 hours). The mixture was filtered and the filtrate flash evaporated to dryness to leave an oil, which upon dilution with toluene and reconcentration to dryness gave colorless crystalline material, m.p. 117°-125°. Two recrystallizations from ethanol raised the m.p. to 139°-141°. This material was combined with product of similar purity which separated from the first ethanolic mother liquor, and the lot recrystallized from cyclohexane to give the analytical sample, m.p. 138.5°-140°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH2:9].[N:10]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=1)=[C:11]=[O:12]>>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:10][C:11]([NH:9][CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:12])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: NCCc1ccccn1
Reactant: CC(C)c1ccc(N=C=O)cc1
Product: CC(C)c1ccc(NC(=O)NCCc2ccccn2)cc1
Yield: 50 %

Procedure:
Prepared in a similar manner to example 158 using 2-(pyridine-2-yl)ethanamine and 1-isocyanato-4-isopropylbenzene. Purified via column chromatography (1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2) to afford 1-(4-isopropylphenyl)-3-(2-(pyridine-2-yl)ethyl)urea (130 mg, 50%) as a white solid. mp: 72-73° C. 1H NMR (500 MHz, CDCl3): δ 1.25 (d, 6H), 2.89 (m, 1H), 3.06 (t, 2H), 3.70 (t, 2H), 5.80 (br s, 1H), 6.55 (br s, 1H), 7.19 (m, 5H), 7.24 (d, 1H), 7.68 (dt, 1H), 8.46 (d, 1H). MS (M+H, 284).
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NCCC)[N:3]1[CH:22]([C:27]([CH3:29])=[CH2:28])[C:23]([O:25][CH3:26])=[O:24].[ClH:30]>C(Cl)Cl>[Cl:30][C:27]1([CH3:29])[CH:22]([C:23]([O:25][CH3:26])=[O:24])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17][CH2:28]1
Reactant: Cl
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNCCC
Solvent: ClCCl
Product: COC(=O)C1N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SCC1(C)Cl
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenylazetidine-1-acetate (0.43 g) was dissolved in dried methylene chloride. To this solution was added 5% methanolic hydrochloric acid (2ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methy 3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (310 mg).