Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.O.[CH:9]1([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@H:28]2[C@@H:32]3[O:33]C(C)(C)[O:35][C@@H:31]3[C@@H:30]([CH2:38][CH2:39][S:40]([NH2:43])(=[O:42])=[O:41])[O:29]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1>>[C@@H:9]1([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@@H:28]2[O:29][C@H:30]([CH2:38][CH2:39][S:40]([NH2:43])(=[O:42])=[O:41])[C@@H:31]([OH:35])[C@H:32]2[OH:33])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CCS(N)(=O)=O)O[C@H]2n1cnc2c(NC3CCc4ccccc43)ncnc21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)CC[C@H]1O[C@@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 0.42 h
Yield: 45 %

Procedure:
Trifluoroacetic acid (3.60 mL, 0.0467 mol) was added to water (0.40 mL, 0.022 mol) and the mixture was added to 2-[(3aR,4R,6R,6aR)-6-(6-(indan-1-ylamino)-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-ethanesulfonamide (crude, 0.000111 mol). The reaction was left to stand (with occasional shaking) for 25 minutes. The reaction was concentrated in vacuo to dryness and the residue purified by preparative HPLC to yield the title compound 23 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[C:10](#[N:13])[CH:11]=[CH2:12].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:12][CH2:11][C:10]#[N:13])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: C=CC#N
Reactant: Cc1cccc(C)c1O
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(CCC#N)cc(C)c1O

Procedure:
In a modification of this Friedel-Crafts reaction, 2,6-di-methylphenol is treated with acrylonitrile in the presence of aluminum chloride to yield 3-(3,5-dimethyl-4-hydroxyphenyl)propionitrile. Upon hydrolysis of this and esterification of the resulting free acid with methanol and p-toluenesulfonic acid, there is obtained methyl 3-(3,5-dimethyl-4-hydroxyphenyl)propionate, M.P. 70°-83° C.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH2:16])[NH:10][N:9]=2)=[CH:3][CH:2]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>CCO.N1CCCCC1>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([N:16]=[CH:28][C:27]3[CH:30]=[CH:31][C:24]([OH:23])=[CH:25][CH:26]=3)[NH:10][N:9]=2)=[CH:3][CH:2]=1
Reactant: NC(=O)c1c(Nc2ccc(-c3ccccc3)cc2)n[nH]c1N
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(-c3ccccc3)cc2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
3-([1,1′-biphenyl]-4-ylamino)-5-amino-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-([1,1′-biphenyl]-4-ylamino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[C:53](I)=[CH:52][CH:51]=[CH:50][N:49]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[Cl:47][C:48]1[C:53]([N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)=[CH:52][CH:51]=[CH:50][N:49]=1
Reactant: C1COCCN1
Reactant: Clc1ncccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Clc1ncccc1N1CCOCC1
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
A 2-dram vial equipped with a stirbar was charged with Pd(OAc)2 (0.234 g, 1.044 mmol) and rac-BINAP (0.683 g, 1.096 mmol) as solids. Toluene (4 mL) was added via syringe, and the mixture was stirred for 10 min while being degassed with argon, and until a uniform tan suspension resulted. A 100-mL round-bottom flask was charged with 2-chloro-3-iodopyridine (1.25 g, 5.22 mmol) and Cs2CO3 (7.14 g, 21.93 mmol). Toluene (34.8 mL) was added followed by morpholine (0.542 ml, 6.26 mmol). This solution was degassed for 1 min under argon, and then the catalyst/ligand suspension was added via pasteur pipette. A reflux condenser was attached to the flask, and the reaction mixture was refluxed at 120° C. for 16 h. The reaction mixture was concentrated in vacuo, and then diluted with CH2Cl2 (150 mL). The organics were washed with 2×100 mL brine, dried over Na2SO4, filtered, and concentrated in vacuo. The material was purified by gradient elution on silica gel (5 to 75% [5% MeOH/EtOAc] in hexanes) to afford the title compound as light yellow solid (700 mg, 64%). Data for 2-1: 1H NMR (500 MHz, CDCl3) d 8.08 (dd, J=4.4, 1.5 Hz, 1H), 7.32 (dd, J=7.8, 1.5 Hz, 1H), 7.21 (dd, J=7.8, 4.5 Hz, 1H), 3.89 (dd, J=4.5, 4.5 Hz, 4H), 3.08 (dd, J=4.5, 4.5 Hz, 4H); HRMS m/z (M+H) 199.0630 found, 199.0633 required.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:15])=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:7]=1.Cl.[CH2:17](O)[CH3:18]>>[CH2:17]([O:12][C:11](=[O:13])[CH2:10][CH2:9][C:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:15])=[O:14])[CH3:18]
Reactant: O=C(O)CCC(=O)c1cc(Cl)ccc1O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCC(=O)c1cc(Cl)ccc1O

Procedure:
A solution of 4-(5-chloro-2-hydroxy-phenyl)-4-oxo-butyric acid (0.25 g, 1.09 mmol) in ethanol (10 mL) saturated with hydrogen chloride (g) was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo, dissolved in diethyl ether and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.259 g).
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[S:7](=[O:18])(=[O:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+]>CCOC(C)=O>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[S:7](=[O:17])(=[O:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCS(=O)(=O)c2ccc([N+](=O)[O-])cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCS(=O)(=O)c2ccc(N)cc21
Temperature: 25 °C

Procedure:
To a suspension of 4-acetyl-6-nitro-3,4-dihydro-2H-1,4-benzothiazine 1,1-dioxide (1.6 g, 5.92 mmol) in EtOAc (21 mL) was added SnCl2-2H2O (6.68 g, 29.6 mmol) and the mixture was heated at reflux for 1.5 h. After this time the reaction mixture was cooled to rt and treated with 2N sodium bicarbonate (30 mL). The resulting solid was filtered and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Mg2SO4, filtered and evaporated in vacuo to give 4-acetyl-3,4-dihydro-2H-1,4-benzothiazin-6-amine 1,1-dioxide. Mass Spectrum (ESI) m/e=241 (M+1).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[CH2:11][CH:12]([CH3:28])[CH2:13][C@@H:14]1[CH2:18][N:17]([C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1>C(Cl)Cl>[F:7][CH2:11][CH:12]([CH3:28])[CH2:13][C@@H:14]1[CH2:18][N:17]([C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(CO)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Solvent: ClCCl
Product: CC(CF)C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: -78 °C
Yield: 37 %

Procedure:
To DAST (1 g, 6.2 mmol) in CH2Cl2 (20 mL) at −78° C. was added the alcohol 37 in CH2Cl2 (10 mL). After 1 hour at −78° C. the solution was warmed to room temperature. After 7 hours the solution was carefully quenched with a saturated aqueous solution of sodium bicarbonate and the two layers separated. The organic phase was dried (MgSO4) and concentrated. Flash chromatography (90% to 66% hexane/acetone) of the residue gave the product as an oil (600 mg, 37%). MS m/z 264 (M+H, 100%).
Reaction SMILES: OO.[OH-].[Li+].C([C@@H]1COC(=O)N1[C:18](=[O:38])[C@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:25]=1)[CH:20]([CH3:22])[CH3:21])C1C=CC=CC=1.S([O-])([O-])=[O:40].[Na+].[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.O>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C@H:19]([CH:20]([CH3:21])[CH3:22])[C:18]([OH:38])=[O:40])=[CH:25][C:26]=1[O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37]
Reactant: O=S([O-])[O-]
Reactant: COCCCOc1cc(C[C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C(C)C)ccc1OC
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(C[C@@H](C(=O)O)C(C)C)ccc1OC
Temperature: 0 °C

Procedure:
With ice-cooling, a 30% hydrogen peroxide solution (434 ml) and lithium hydroxide 98% (31.2 g) are added to a solution of 4(R)-benzyl-3-{2(R)-[4-methoxy-3-(3-methoxypropoxy)-benzyl]-3-methyl-butyryl}-oxazolidin-2-one (300 g) in tetrahydrofuran/water 3:1 (4.8 liters). When the addition is complete, the temperature of the reaction mixture is allowed to rise to room temperature over the course of 3 hours; the batch is then cooled again to 0° C. and a 1.5M aqueous sodium sulfite solution (2.55 liters) and then a saturated aqueous sodium hydrogen carbonate solution (1 liter) are added dropwise over the course of 30 minutes. The mixture is concentrated under reduced pressure and the aqueous solution so obtained is washed with dichloromethane (3×3 liters). The aqueous phase is adjusted to pH 3 by the addition of 2N hydrochloric acid, extracted with dichloromethane (3×3 liters), and the combined organic phases are dried over magnesium sulfate and concentrated. The title compound is obtained in the form of an oil (186.8 g), which can be caused to crystallise in hexane/diethyl ether at -20° C.: m.p. 43.5°-44° C. Rf (ethyl acetate/hexane 2:1)=0.30. Anal. C17H26O5 (310.39): calc. C, 65.78; H, 8.44; found C, 65.96; H, 8.70.
Reaction SMILES: [I-].C[S+](C)C.[OH-].[K+].[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[CH:20]=[O:21].[CH:22]1C=CC=CC=1>C(#N)C.O>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[CH:20]1[CH2:22][O:21]1
Reactant: c1ccccc1
Reactant: COc1ccc2nccc(C=O)c2c1
Agent: C[S+](C)C
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccc2nccc(C3CO3)c2c1
Temperature: 60 °C

Procedure:
Trimethylsulphonium iodide (0.954 g, 4.67 mmol) and potassium hydroxide powder (1.8 g, 32 mmol) were added to a solution of 6-methoxy-quinoline-4-carbaldehyde (0.85 g, 4.54 mmol) in acetonitrile (13.5 ml) and water (6 drops). The reaction mixture was heated at 60° C. for one hour. The mixture was then cooled to room temperature and benzene (40 ml) was added. The precipitate was filtered off and the filtrate was concentrated to dryness by rotary evaporation. The residue was diluted with water (100 ml) and ethyl acetate (100 ml), the phases were separated, and the aqueous phase was extracted twice using 50 ml of ethyl acetate each time. The combined organic phases were dried over MgSO4, filtered and concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (EtOAc).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]Cl.C(O)CCCCC.[OH-].[Na+]>ClC1C=CC=CC=1Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: ClCCNCCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCCO
Solvent: Clc1ccccc1Cl
Product: c1cnc2c(N3CCNCC3)cccc2c1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
A mixture of 8-aminoquinoline (1.5 g), bis-(2-chloroethyl)amine hydrochloride (2.04 g), o-dichlorobenzene (4.5 mL) and n-hexanol (0.45 mL) was stirred at reflux temperature for 5 h. After cooling to room temperature, the mixture was treated with 2 N NaOH (10 mL) and extracted with CH2Cl2 (3×20 mL). The purification was carried out by flash chromatography (CH2Cl2-2 N methanolic NH3) 97:3 to give 0.48 g (22%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]([CH2:22][CH2:23]O)[C:10](=[O:21])[NH:11][C@@H:12]([CH3:20])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:58]([OH:61])(=[S:60])[CH3:59].C(=O)([O-])O.[Na+]>O1CCCC1>[C:58]([S:60][CH2:23][CH2:22][N:9]([CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:10](=[O:21])[NH:11][C@@H:12]([CH3:20])[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])(=[O:61])[CH3:59]
Reactant: CC(O)=S
Reactant: C[C@H](NC(=O)N(CCO)CCC1CCCCC1)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)SCCN(CCC1CCCCC1)C(=O)N[C@@H](C)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
Anhydrous tetrahydrofuran (6 ml) is added to a mixture of t-butyl (2S)-2-[3-(2-cyclohexylethyl)-3-(2-hydroxyethyl)ureido]propionate (Compound No. 1-1, 1.0 g) and triphenylphosphine (1.5 g) under a nitrogen atmosphere, and the mixture is stirred for 30 minutes under salt-ice cooling. Diisopropyl azodicarboxylate (1.2 ml) is added dropwise to the mixture while keeping liquid temperature at 5° C., and then thioacetic acid (0.4 ml) is added dropwise thereto over 20 minutes. The mixture is stirred for 20 minutes, a 10% aqueous sodium hydrogencarbonate solution (30 ml) is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with a 10% aqueous sodium hydrogencarbonate solution, water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily matter is purified by silica gel column chromatography to give the titled compound (Compound No. 5-1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)[CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[C:53](OC(=O)C)(=[O:55])[CH3:54]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:53]([NH:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH2:46][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]3)[CH2:41]2)=[O:37])=[O:30])[CH2:3]1)(=[O:55])[CH3:54]
Reactant: N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of 22 mg of (2R)-1-{(2S,4S)-4-amino-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-{((3R)-1-cyclohexylmethyl-3-piperidyl)methyl}pyrrolidine-2-carboxamide in 1 ml of chloroform, 0.0089 ml of acetic anhydride and 0.0127 ml of pyridine were added at room temperature, followed by an hour's stirring at the same temperature. The reaction liquid was diluted with chloroform, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After distilling the solvent off under reduced pressure, the resulting residue was purified with a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol=8/1), to provide 18 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1F
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Temperature: 100 °C
Yield: 65.2 %

Procedure:
1-Fluoro-2-nitrobenzene (50.0 g, 0.354 mol) was added to chlorosulfonic acid (91 g, 0.778 mol) at 65° C. The resulting mixture was then heated to 100° C. for 18 h. The mixture was cooled to room temperature, poured over ice and extracted with methylene chloride. The combined organic layers were then washed with NaHCO3, then brine, dried over MgSO4, filtered and concentrated in vacuo to afford 4-fluoro-3-nitrobenzenesulfonyl chloride (55.3 g, 65% yield) as a brown oil.
Reaction SMILES: [C@@H:1]([C@@H:5]1[NH:6][C:7](=[O:20])[C:8]2[C:13](/[C:14]/1=[CH:15]/[C:16]([O:18]C)=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:3][CH3:4])[CH3:2].C1COCC1.O.[Li+].[OH-].Cl>O.C1COCC1>[C@@H:1]([C@@H:5]1[NH:6][C:7](=[O:20])[C:8]2[C:13](/[C:14]/1=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=[CH:10][CH:9]=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@H](C)[C@@H]1NC(=O)c2ccccc2/C1=C/C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]1NC(=O)c2ccccc2/C1=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 7 (273 mg, 1.0 mmol) in a 1:1 mixture of THF—H2O (10 mL) at room temperature was added a solution of LiOH (83.9 mg, 2.0, mmol) in H2O (2 mL). The mixture was stirred at room temperature overnight, and was then acidified with 5% HCl to pH=2. THF was eliminated in vacuo and the aqueous phase was extracted with EtOAc (3×50 mL). The organic phases were washed with brine and dried over MgSO4. Once the solvent had been eliminated in vacuo the raw product was obtained, which was purified by recrystallisation of EtOAc/hexane to give the acid 8 (140 mg, 54% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (0.20 g, 0.72 mmol) in dry DCM (20 mL) were added tert-butyl (3S)-3-(aminooxy)piperidine-1-carboxylate 16 (0.19 g, 0.86 mmol, J, Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.14 g, 1.03 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.03 mmol) at room temperature, The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl (3S)-3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]piperidine-1-carboxylate 17 (0.28 g, 82%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].[ClH:15]>CO.[Pd]>[ClH:15].[NH2:11][CH2:10][C:9]1[CH:8]=[C:7]([N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1cccc(N2CCNC2=O)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccc(N2CCNC2=O)c1

Procedure:
40.00 g (210 mmol) 3-(2-oxo-imidazolidin-1-yl)-benzonitrile are suspended in 1500 ml of methanol, 53 ml of 37% hydrochloric acid are added. The mixture is hydrogenated for 20 hours at ambient temperature under a pressure of 7 bar with 4.00 g palladium/charcoal. The catalyst is filtered off, the filtrate is concentrated and the precipitate formed is suction filtered, washed with acetone and dried.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]([NH2:13])=O)=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1.S(Cl)(Cl)=O>CN(C=O)C>[Cl:1][C:2]1[C:3]([C:11]#[N:13])=[N:4][C:5]([CH2:9][CH3:10])=[C:6]([Cl:8])[N:7]=1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCc1nc(C#N)c(Cl)nc1Cl
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
To a mixture of 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.0 g) and DMF (15 mL), thionyl chloride (1 mL) was added at room temperature and stirred for 20 minutes. The reaction liquid was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane) to give 3,5-dichloro-6-ethylpyrazine-2-carbonitrile (608 mg) as a slightly yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=[O:12].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][CH2:24][CH:25]([O:37][Si](C(C)(C)C)(C)C)[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=2)[CH:18]=1.F>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[OH:37][CH:25]([CH2:24][CH2:23][C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:8]2[CH:16]=[CH:15][CH:14]=[C:10]([C:11]([NH2:13])=[O:12])[CH:9]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCc1cccnc1)COc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: F
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CC#N
Product: NC(=O)c1cccc(-c2ccc(OCC(O)CCc3cccnc3)cc2)c1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
Prepared according to the method described in Example 33a) from toluene (3 ml), aqueous sodium carbonate (2 M, 1.4 ml), ethanol (0.8 ml), 3-bromobenzamide (0.5 g), (±)-4-[4-(3-pyridyl)-2-(tert-butyldimethylsilyloxy)butoxy]benzeneboronic acid (1.0 g) and tetrakis(triphenylphosphine)palladium(0) (70 mg) with heating at 120° C. for 3 hours. The residue obtained after work up was purified by column chromatography over silica eluting with 5% ethanol in dichloromethane to give a yellow gum which was deprotected as in Example 34e) using hydrofluoric acid (40%, 5 ml, CAUTION) in acetonitrile (20 ml). The residue obtained after work up was triturated with diethyl ether to give the title compound as a pale yellow solid (0.224 g)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:11]1[C:15]2([NH:24][C:18]3([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[O:17][CH2:16]2)[CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>C1COCC1.O>[CH:18]1([NH:24][C:15]2([CH2:16][OH:17])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: C1CCC2(CC1)NC1(CCCC1)CO2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCC1(NC2CCCCC2)CCCC1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 78.5 %

Procedure:
To a solution of LiAlH4 (0.93 g, 24.4 mmol) and AlCl3 (3.24 g, 24.4 mmol) in THF at 4° C. was added dropwise a solution of 14-aza-7-oxadispiro[4.2.5.1]tetradecane (2.38 g, 12,2 mmol) in THF (15 mL). The resulting mixture was warmed to 20° C. and stirred for 45 min., then cooled to 4° C. Water (5 mL) was slowly added to quench the reaction and a 1N NaOH solution (85 mL) was added to dissolve the resulting solids. The resulting solution was extracted with Et2O (200 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield 1-(cyclohexylamino)-1-(hydroxymethyl)cyclopentane 1.89 g (79%): GC-MS m/z 197 (M+).