Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[O:20]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21]1>C(O)CCC>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:25][CH:22]1[CH2:23][CH2:24][O:20][CH2:21]1)([O-:19])=[O:18]
Reactant: NC1CCOC1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1NC1CCOC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N,N-diisopropylethylamine (3.20 mL, 18.4 mmol), 1-fluoro-2-nitrobenzene (0.484 mL, 4.59 mmol), and (±)-tetrahydrofuran-3-amine (400 mg, 4.59 mmol) in n-butanol (10 mL) was heated to 180° C. in a microwave reactor. After 20 min, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, gave the title compound. MS: m/z=209 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[CH2:9]=[O:10]>O>[CH2:1]([N:3]([CH2:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCNC(=O)OCC
Reactant: C=O
Solvent: O
Product: CCOC(=O)N(CC)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Under general experimental conditions reported by Kelper, JOC, 52, 453-55 (1987), a slurry of Ba(OH)2 (46.0 mg, 266 μmol) in water (480 μL) was added to a mixture of N-ethylurethane (2.04 mL, 17.1 mmol) and a 37% aqueous solution of formalin (1.28 mL, 17.1 mmol) in one portion with stirring. The mixture became cool and gradually formed a cloudy solution. The mixture was stirred at room temperature and the disappearance of N-ethylurethane monitored by TLC analysis. After 2 h, the reaction was quenched by adding solid CO2, stirred for 30 minutes and filtered to remove the precipitated barium carbonate. The solvent was removed under vacuum to provide an oily residue. The trace amounts of water were removed by azeotropic distillation with benzene (3×100 mL) to provide 56 as a clear oil (2.50 g, quant.): 1H NMR (400 MHz, CDCl3) δ 4.88 (d, J=7.6 Hz, 1H), 4.79 (d, J=7.6 Hz, 2H), 4.18 (q, J=7.6 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H), 1.19 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11]N1C(=O)CCC1=O>CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COc1ccc(CBr)cc1Cl
Temperature: 25 °C
Yield: 104.6 %

Procedure:
3-Chloro-4-methoxytoluene 8 (2.6 mL, 19.2 mmol) was dissolved in dichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 21.1 mmol) was added followed by AIBN (36.0 mg). The reaction was heated to reflux for 19 hrs., then cooled to room temperature and the precipitate was filtered off. The filtrate was diluted with dichloromethane and washed with 0.5 M aqueous sodium bicarbonate, followed by water. The organic mixture was dried over sodium sulfate, filtered and concentrated under vacuum to yield 9 (4.73 g, 82%). The benzyl bromide was used as the crude material without further purification.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[F:12][C:13]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([CH3:23])[NH:17]2.[Cl:24][C:25]1[N:30]=[C:29](Cl)[CH:28]=[CH:27][N:26]=1>CC#N>[Cl:24][C:25]1[N:30]=[C:29]([O:22][C:21]2[C:13]([F:12])=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([CH3:23])=[CH:15]3)[CH:28]=[CH:27][N:26]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1cc2c(F)c(Oc3ccnc(Cl)n3)ccc2[nH]1
Temperature: 23 °C
Reaction time: 15 h

Procedure:
DBU (5.48 mL, 36.3 mmol) is added dropwise to a suspension of 4-fluoro-2-methyl-1H-indol-5-ol (5.00 g, 30.3 mmol) and 2,4-dichloropyrimidine (4.60 g, 30.9 mmol) in CH3CN (60 mL) at 0° C. The resulting mixture is warmed to and stirred at 23° C. for 15 h. The reaction mixture is concentrated and the residue is partitioned between 1:1 EtOAc-CH2Cl2 (300 mL) and water (150 mL). The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (100 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to provide 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Br:15]Br>C(O)(=O)C.O.[Fe]>[Br:15][C:8]1[CH:7]=[C:6]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccncc2)cc1
Reactant: BrBr
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2ccncc2)cc1Br
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4-(4-Methoxyphenyl)pyridine (1 g, 5.4 mmol) was dissolved in glacial acetic acid (6 ml). Iron powder (30 mg, 0.54 mmol) was added followed by a solution of bromine (0.36 ml) in glacial acetic acid (3 ml) slowly over 5 minutes. The resulting solution was stirred at 60° C. for 1 hour. A solution of bromine (0.13 ml) in glacial acetic acid (1 ml) was added and stirring was continued at 60° C. for 1.5 hours. The solution was allowed to cool to ambient temperature, diluted with water (20 ml). Excess bromine was destroyed by adding in sold sodium bisulphite until all the colour had disappeared. Solid sodium carbonate was added until the solution was basic and the resulting solution was then extracted with ethyl acetate (2×30 ml) and dried over sodium sulphate. Removal of the solvent gave an oil which was chromatographed on silica gel in diethyl ether giving the title compound as a clear oil (0.77 g, 54%). 1H NMR (250 MHz, CDCl3) δ 8.66-8.62 (2H, d, J=8.6 Hz), 7.87-7.86 (1H, d, J=2.2 Hz), 7.61-7.56 (1H, dd, J=8.5 Hz and 2.2 Hz), 7.48-7.46 (1H, d, J=8.5 Hz), 7.03-6.99 (2H, d, J=8.6 Hz), and 3.96 (3H, s). m/z (ES+) 264, 266 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].CN1CCOCC1>CC#N>[CH2:1]([O:8][C:9](=[O:16])[C@H:10]([CH2:12][CH:13]([CH3:14])[CH3:15])[NH:11][C@@H:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(C)Br
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](C)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Yield: 25.8 %

Procedure:
L-Leucine benzyl ester (186.65 g, 0.843M), ethyl 2-bromopropionate (153.1 g, 0.846M) and N-methylmorpholine (165 ml, 1.5M) were dissolved in dry CH3CN (800 ml) and refluxed for 12 h. The solvent was removed in vacuo and the residue partitioned between H2O (21) and EtOAc (3×11). The organic phase was washed with brine, dried and evaporated in vacuo. The resulting oil was chromatographed on SiO2 in 7.5% EtOAc in hexane to give the title compound (70 g) as the faster running fraction; (Found: C,67.02; H,8.42; N,4.25; C18H27NO4 requires C,67.26; H,8.47; N,4.36); νmax film 1730 cm-1 ; δ (CDCl3) 0.88 and 0.9 (each 3H, each d, each J=6.5 Hz, CH(CH3)2) 1.23 (3H,t,J=7 Hz,CH3CH2O), 1.27 (3H,d,J=7 Hz,CH3CH), 1.5 (2H,m,CHCH2), 1.7 (1H, heptet, J=7 Hz, CH(CH3)2), 2.2 (1H, br s,NH), 3.32 (2H,m, CHNHCH), 4.10 and 4.12 (each 1H, each q, each J=7 Hz, OCH2CH3), 5.12 (2H,s, OCH2C6H5) and 7.34 (5H,s, C6H5); m/e 322 (100%; [m+1])+, 260 (15), 186 (26) and 112 (28).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@H:24]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:25]([N:27]([CH3:32])[NH:28][C:29](=[O:31])[CH3:30])=[O:26])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:29]([NH:28][N:27]([C:25](=[O:26])[C@H:24]([N:22]([CH3:23])[C:21](=[O:40])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH3:32])(=[O:31])[CH3:30]
Reactant: CC(=O)NN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)NC(C)=O
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
To a solution of N-((1R)-1-(N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (0.14 g, 0.25 mmol) in methylene chloride (2 ml) at 0° C. was added trifluoroacetic acid (2 ml) and the mixture was stirred for 90 min. Then methylene chloride (50 ml) and saturated sodium bicarbonate (5 ml) was added and the mixture was titrated with solid sodium bicarbonate until pH=7. The water layer was separated and extracted with methylene chloride (20 ml) and the combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered and concentrated in vacuo to give 0.10 g (87%) of (2R)-N-[(1R)-2-(N'-acetyl-N-methylhydrazino)-1-benzyl-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide as an oil.
Reaction SMILES: [C:1]1(=[C:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21](COCC[Si](C)(C)C)[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1(=[C:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][NH:21][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)=C4CCCC4)c3)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC(=C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A solution of 3-cyclopentylidene-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.030 g, 0.069 mmol) in DCM (3 mL) and TFA (2 mL) was stirred for 1 hour. The solvents were evaporated in vacuo and the product was stirred with sodium hydroxide, 50% aqueous solution (0.75 mL) and water (0.75 mL) and THF (1.5 mL) for 2 hours. The reaction mixture was neutralized by dropwise addition of concentrated HCl. The product was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative-HPLC/MS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to afford the desired product (7 mg, 33%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([F:11])([F:10])[C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:14]O>>[CH3:5][OH:6].[F:1][C:2]([F:12])([F:13])[C:3]([F:10])([F:11])[C:4]([F:8])([F:9])[C:5]([O:7][CH3:14])=[O:6]
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CO
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
In the specific embodiment herein described employing methanol and heptafluorobutyric acid as reactants, distillation of the resulting esterification reaction admixture results in a methanol/methyl heptafluorobutyrate azeotrope characterized by a boiling point of about 56°-58° C. at substantially atmospheric pressure. This azeotrope also is characterized by about 78-80 weight percent methyl heptafluorobutyrate and correspondingly about 22-20 weight percent methanol. It is noted that the specific azeotrope of my discovery is a minimum boiling azeotrope boiling at a temperature substantially below both the boiling point of methanol, 65° C., and of methyl heptafluorobutyrate, 80° C.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[F:28][C:25]([F:26])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][CH:16]1[CH2:17][NH:14][CH2:15]1
Reactant: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(OC2CNC2)c1
Reaction time: 3 h

Procedure:
44 mg of 10% palladium on charcoal was added to a solution of 0.23 mmol 1-benzhydryl-3-(3-trifluoromethyl-phenoxy)-azetidine in 5 ml acetic acid. The reaction mixture was hydrogenated for 3 hours at room temperature and normal pressure. Filtration and concentration yielded the crude product which was used in the next step without further purification. MS (m/e): 218.2 (M+H+, 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C)C=O.C(N(CC)CC)C.[NH2:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]2>S(Cl)(Cl)=O.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:28][C:29]4[CH:30]=[C:31]5[C:35](=[CH:36][CH:37]=4)[NH:34][C:33]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:32]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
1-Benzo[1,3]dioxol-5-yl-cyclopropanecarboxylic acid (2.07 g, 10.0 mmol) was dissolved in thionyl chloride (2.2 mL) under N2. N,N-dimethylformamide (0.3 mL) was added and the solution was allowed to stir for 30 minutes. The excess thionyl chloride was removed under vacuum and the resulting solid was dissolved in anhydrous dichloromethane (15 mL) containing triethylamine (2.8 mL, 20.0 mmol). Ethyl 5-amino-1H-indole-2-carboxylate (2.04 g, 10.0 mmol) in 15 mL of anhydrous dichloromethane was slowly added to the reaction. The resulting solution was allowed to stir for 1 hour. The reaction mixture was diluted to 50 mL with dichloromethane and washed three times with 50 mL of 1N HCl, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and evaporated to dryness to yield ethyl 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-1H-indole-2-carboxylate as a gray solid (3.44 g, 88%). ESI-MS m/z calc. 392.4; found 393.1 (M+1). Retention time 3:17 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 8.64 (s, 1H), 7.83 (m, 1H), 7.33-7.26 (m, 2H), 7.07 (m, 1H), 7.02 (m, 1H), 6.96-6.89 (m, 2H), 6.02 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 1.42-1.39 (m, 2H), 1.33 (t, J=7.1 Hz, 3H), 1.06-1.03 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([Cl:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[H][H].C(Cl)Cl.CO>C1COCC1>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([Cl:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1OCc1ccccc1
Reactant: [H][H]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1O
Reaction time: 12 h

Procedure:
200 mg 5% Rh on aluminium oxide were added to a solution of 800 mg (1.35 mmol) (R)-2-(4-benzyloxy-3-chloro-5-methyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 20 mL THF and the suspension was hydrogenated for 12 h at 40° C. and 3000 hPa hydrogen pressure. To complete the reaction the mixture was combined with 5 mL DCM/MeOH (1:1) and hydrogenated for a further 20 h at 40° C. and 3000 hPa. The catalyst was filtered off, the filtrate was evaporated down, the residue was triturated with DIPE, suction filtered and dried.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][C:17](=O)[CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([CH2:33][N+:34]#[C-])(C1C=CC(C)=CC=1)(=O)=O.C(O)C>C(COC)OC>[C:33]([CH:17]1[CH2:16][CH:15]2[N:14]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:19]([CH2:20][CH2:21]2)[CH2:18]1)#[N:34]
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Solvent: COCCOC
Product: N#CC1CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
Potassium t-butoxide (2.5 g) was added portionwise to a stirred mixture of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (2.0 g), tosylmethyl isocyanide (2.36 g) and ethanol (2 ml) in dimethoxyethane (50 ml) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 0.5 hours and then overnight at room temperature. The mixture was then filtered and the solid residue washed with dimethoxyethane. The combined filtrates were evaporated under reduced pressure and chromatographed [SiO2; hexane:ethyl acetate (80:20)] to give 3-cyano-8-benzyl-8-azabicyclo[3.2.1]octane (0.87 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:13]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)cc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1cc(Cl)cc(C=O)c1OC
Temperature: 61 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A mixture of 5-Chloro-2-hydroxy-3-methoxybenzaldehyde (275 g, 1.47 mol) and DMF were stirred as potassium carbonate (411 g, 2.97 mol) was added over 5 minutes. The mixture temperature rose from 22 to 29° C. over 10 minutes. Dimethylsulfate (283 g, 2.24 mol) was added over 15 minutes causing a temperature rise from 28 to 47° C. The mixture was then heated with a heating mantle to 61° C. over 15 minutes and stirred at 61° C. for 1.5 hours; the reaction was complete by TLC. The reaction mixture was cooled to 22° C., transferred to a 22-L flask and diluted with water (8.2 L) over 5 minutes; the temperature rose to 38° C. The light yellow mixture was filtered and the flask and filter cake rinsed with 1.5 L water. The solid was dried under vacuum for 15 hour at 50° C. The material contained inorganic salts and was suspended in water (3 L) for 1.5 hours. After filtration and a 500 mL water rinse, the filter cake was dried under by suction and overnight at 65° C. under vacuum. Yield: 305 g (100% yield, 99.1% purity).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C[Si](C)(C)Cl>CN1CCCC1=O>[CH2:20]([O:27][C:28](=[O:60])[CH2:29][CH2:30][C:31]([O:33][C:34]1([CH2:40][O:41][C:42]2[CH:47]=[CH:46][C:45]([N:48]3[CH2:52][C@H:51]([CH2:53][NH:54][C:55](=[O:57])[CH3:56])[O:50][C:49]3=[O:58])=[CH:44][C:43]=2[F:59])[CH2:39][CH2:38][N:37]([C:2]2[C:3]([F:19])=[CH:4][C:5]3[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]([CH:12]4[CH2:14][CH2:13]4)[C:10]=3[N:11]=2)[CH2:36][CH2:35]1)=[O:32])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCNCC3)c(F)c2)C(=O)O1
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 1 step 7, with 113 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (MW: 282.66, 0.4 mmol), 230 mg succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-piperidin-4-yl ester benzyl ester (MW: 571.60, 0.4 mmol), 161 mg triethylamine (MW: 101.19, 1.6 mmol) and 87 mg trimethylchlorsilan (MW: 108.64, 0.8 mmol) in 2 ml N-methyl-pyrrolidin-2-one. Yield: 25 mg, 7.6%. MS: 819 (M+H)+, 817.8, Method ESI+, ESI−.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[C:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH2:3][CH3:4].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.CO>[CH2:1]([N:5]1[C:9]([CH2:10][CH3:11])=[CH:8][CH:7]=[C:6]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:21]([NH2:22])=[O:20])[CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(CC)ccc1Cc1cccc(N)c1
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CCCCn1c(CC)ccc1Cc1cccc(NC(N)=O)c1
Yield: 94.6 %

Procedure:
A stirred solution of 3.1 g (12 mmol) of 1-butyl-2-(3'-aminobenzyl)-5-ethylpyrrole in 250 ml of dry methylene chloride and 50 ml of anhydrous methanol was treated, at room temperature and under nitrogen atmosphere, with 1.7 g (26 mmol) of sodium cyanate, followed by the dropwise addition, over a 2 hour period, of 2.3 ml (29 mmol) of trifluoroacetic acid in 100 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 additional hours, 2 g (18 mmol) of sodium carbonate were then added and the solvent evaporated under reduced pressure. The residue was purified by column chromatography on 300 g of silica gel, using methylene chloride-methanol (97:3) as eluant, thus obtaining 3.4 g (93%) of the title compound, 1-butyl-2-(3'-ureidobenzyl)-5-ethylpyrrole, which was recrystallized from ether-hexane.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(NC(COCc1ccccc1)C(=O)O)OCCNc1ccccn1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCNc1ccccn1)c1cc(Cl)cc(Cl)c1

Procedure:
Analogously to Example 2, ethyl 3-amino-3-(3,5-dichlorophenyl)propionate is reacted with 3-benzyloxy-2-[2-(pyridin-2-ylamino)ethoxycarbonylamino]-propionic acid and purified by chromatography, giving ethyl 3-{3-benzyloxy-2-[2-(pyridin-2-ylamino)ethoxycarbonylamino]propanoylamino}3-(3,5-dichlorophenyl)propionate, RT 1.712 min, FAB-MS (M+H)+ 604.
Reaction SMILES: [O-]CC.[K+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]>C(OCC)C.C(O)C>[CH2:13]([O:12][C:5](=[O:11])[C:6](=[O:8])[CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[CH3:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1ccncc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of potassium ethoxide (3.1 g, 36.2 mmol) in diethyl ether (70 mL) and ethanol (10 mL) under an argon atmosphere was added diethyl oxalate (4.9 mL, 36.2 mmol) and the reaction stirred at rt for 30 min. A solution of 4-methyl-3-nitropyridine (5.0 g, 36.2 mmol) in diethyl ether (20 mL) was added resulting in the immediate formation of a dark red precipitate. The reaction mixture was stirred at rt for 72 h, then cooled to 0° C. and filtered. The solid was dissolved in water (500 mL) acidified to pH 4 with acetic acid and the precipitate collected and dried to give the title compound as a red solid. δH (d6 DMSO): 1.27 (3H, t), 4.25 (2H, q), 6.74 (1H, s), 8.34 (1H, d), 8.43 (1H, d), 8.98 (1H, s); m/z (ES+)=239 [M+H]+.