Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)(O)[O-].[Na+].[NH2:6][CH:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[CH2:8][C:9](O)=[O:10].FC(F)(F)S(Cl)(=O)=O>C(#N)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH:7]2[NH:6][C:9](=[O:10])[CH2:8]2)[CH:13]=1
Reactant: NC(CC(=O)O)c1cccnc1
Agent: O=C([O-])O
Agent: O=S(=O)(Cl)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: O=C1CC(c2cccnc2)N1
Temperature: 77.5 °C
Reaction time: 19 h
Yield: 41.8 %

Procedure:
To a mixture of 20.20 g (0.24 mole) sodium bicarbonate (Sigma, Ultrapure, dried in good vacuum at room temperature for 3 days over phosphorus pentoxide) and 6.64 g (0.04 mole) 3-amino-3-(pyridine-3-yl)propionic acid (Tyger, dried in good vacuum at room temperature for 3 days over phosphorus pentoxide) under argon atmosphere first 200 ml of dry acetonitrile (Fisher) was added then at very strong stirring 4.7 ml (0.044 mole) trifluormethanesulfonyl chloride (Acros) was slowly added and thereafter the reaction mixture was further stirred in an oil bath of 75-80° C. for 19 hours. After cooling and stirring in ice bath for 1 hour the reaction mixture was filtered, washed three times with dry acetonitrile and the combined organic solutions were evaporated on a rotavapor at 35° C. The solid residue (23.8 g) was extracted in a Soxhlet-type extractor with boiling chloroform for 26 hours. The evaporation of the chloroform solution gave 2.48 g (42%) pure product as white crystalline material (mp: 115-116° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]1[CH2:16][C:15](=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8]1)([O-:3])=[O:2].[CH3:21]N(CN(C)C)C.C(OC(=O)C)(=O)C>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[CH:7]1[C:16](=[CH2:21])[C:15](=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8]1)([O-:3])=[O:2]
Reactant: CN(C)CN(C)C
Reactant: O=C1CC(c2cccc([N+](=O)[O-])c2)Oc2ccccc21
Solvent: CC(=O)OC(C)=O
Product: C=C1C(=O)c2ccccc2OC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 1.35 g (5 mmol) of 3'-nitroflavanone [prepared as described in J. Chem. Soc. Japan, Pure Chem. Sect. 74, 827 (1953)], and 12 ml of bis-(dimethylamino)methane was stirred at room temperature; 12 ml of acetic anhydride was added dropwise over 15 minutes. The temperature rose to 77°. After cooling to ambient temperature, the reaction was partitioned between 100 ml portions of ether and 100 ml portions of cold water. The aqueous phase was separated, washed with two 100 ml of ether, and discarded. The combined ether extracts were washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered and evaporated. The residual oil was chromatographed on 100 g of silica gel, eluting with benzene to yield 548 mg of 3'-nitro-3-methylene flavanone, isolated as a white solid, m.p. 131°-132° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N=C=NC(C)C)(C)C.[NH2:23][NH2:24]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:23][NH2:24])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: NN
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: NNC(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 4-amino-3-nitrobenzoic acid (1.64 g, 9 mmol) in THF (25 mL) was added diisopropylcarbodiimide (1.13 g, 9 mmol). The mixture was stirred at RT for 15 min and to the resulting yellow solution was added hydrazine (600 mg, 18 mmol). The resulting orange suspension was stirred at RT for 2 h. The solid was filtered and washed twice with THF to give the title compound: MS: m/z 195.1 (M−1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]([CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:10]1)=[N+:7]=[N-:8].C(N(CC)CC)C>ClCCl>[N:6]([CH:9]1[CH:13]([O:14][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:10]1)=[N+:7]=[N-:8]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CC(O)C(N=[N+]=[N-])C3)c(F)c2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC(N=[N+]=[N-])C(OS(C)(=O)=O)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (8 μL, 0.10 mmol) was added to a solution of N-({(5S)-3-[4-(3-azido-4-hydroxypyrrolidin-1-yl)-3-fluorophenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (30 mg, 0.08 mmol) and triethylamine (16 μL, 0.12 mmol) in dichloromethane (0.5 mL) at 0° C. After 1 h, the solution was diluted with more dichloromethane, washed with dilute NaHCO3, brine and dried (MgSO4), filtered and concentrated to give the title compound as an oil. This material was used directly in the next reaction.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]([C:11]([OH:13])=[O:12])[NH:2]1.[OH-].[Na+].C(Cl)Cl.O.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([O-:22])=[O:21]>C(Cl)Cl.C(Cl)(Cl)Cl.Cl>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([S:29]([N:2]2[C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)[C@H]1Cc2ccccc2CN1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 3 h
Yield: 37 %

Procedure:
(3R)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid (5.32 g) and sodium hydroxide (2.40 g) are added to a mixture of methylene chloride-water (200 ml--200 ml), and thereto is added dropwise a solution of 4-nitrophenylsulfonyl chloride (6.62 g) in methylene chloride (100 ml) under ice cooling over a period of 30 minutes. The mixture is stirred under ice cooling for 3 hours, and thereto are further added sodium hydroxide (1.20 g) and a solution of 4-nitrophenylsulfonyl chloride (3.32 g) in methylene chloride (60 ml) in this order. The mixture is stirred under ice cooling for 2 hours, and further stirred at room temperature for 17 hours, and the reaction mixture is diluted with chloroform and 10% hydrochloric acid. The chloroform layer is collected and washed with water and then with an aqueous saturated saline solution, dried over sodium sulfate and then treated with active carbon. Undissolved materials are filtered off from the chloroform layer, and the solvent is distilled off under reduced pressure. The residue is purified with a silica gel column chromatography (eluent, chloroform) and recrystallized from ethyl acetate-hexane to give (3R)-N-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (4.01 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH:20][CH3:21])(=[O:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CN(C)C=O.O>[Br:1][C:2]1[C:3]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([NH:20][CH3:21])(=[O:19])=[O:18])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CNS(=O)(=O)c1ccccc1N
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 23 h

Procedure:
A suspension of 5-bromo-2,4-dichloropyrimidine (684 mg, 3.0 mmol) and 2-amino-N-methyl-benzenesulfonamide (559 mg, 3.0 mmol) in N,N-dimethylformamide (10 mL) containing potassium carbonate (830 mg, 6.0 mmol) is stirred at room temperature for 23 hours. Saturated aqueous ammonium chloride is added and the mixture is poured into water and extracted twice with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane-ethyl acetate gradient) to afford the title compound as a slightly yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:17])([F:16])[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)C.O.[NH2:20][NH2:21]>CO>[F:16][C:5]([F:17])([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][CH:10]=[CH:9]2)[C:4]([NH:20][NH2:21])=[O:3]
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Temperature: 45 °C
Yield: 50.6 %

Procedure:
Difluoro-quinolin-6-yl-acetic acid ethyl ester (836 mg, 3.33 mmol) was dissolved in MeOH (13 mL). Hydrazine monohydrate (1.5 mL, 16.8 mmol) was added. The mixture was heated at 45° C. for 30 min, cooled to rt, concentrated, and taken up in DCM. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel column to give the title compound as light orange solid (400 mg, 51%). 1H-NMR (400 MHz, CDCl3). ppm 3.99 (br s, 2H), 7.51 (m, 1H), 7.92 (m, 1H), 8.15 (s, 1H), 8.20-8.26 (q, 2H), 9.02 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH:25][C:26]1[C:31]([CH2:32][CH2:33][CH3:34])=[C:30]([SH:35])[CH:29]=[CH:28][C:27]=1[C:36](=[O:38])[CH3:37].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[C:36]([C:27]1[CH:28]=[CH:29][C:30]([S:35][CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:7]([CH2:22][CH2:23][CH3:24])=[C:8]([C:16]([CH:19]([OH:21])[CH3:20])=[CH:17][CH:18]=2)[O:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:31]([CH2:32][CH2:33][CH3:34])[C:26]=1[OH:25])(=[O:38])[CH3:37]
Reactant: CCCc1c(OCCCCl)ccc(C(C)O)c1OCCCC(=O)O
Reactant: CCCc1c(S)ccc(C(C)=O)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(SCCCOc2ccc(C(C)O)c(OCCCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 25.4 %

Procedure:
A mixed solution of 42.6 mg of (+)-4-[3-(3-chloropropoxy)-6-(1-hydroxyethyl)-2-propylphenoxy] butanoic acid, 30.0 mg of (2-hydroxy-4-mercapto-3-propylphenyl) ethanone, 39.4 mg of potassium carbonate and 1 ml of dimethylformamide was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. After washed with water and saturated aqueous solution of sodium chloride, the organic layer was dried over anhydrous sodium sulfate and subjected to distillation off of the solvent under reduced pressure to afford residue. The residue was purified through silica gel column chromatography (methylene chloride: ethanol=20:1) and further through preparative thin layer chromatography (methylene chloride: methanol=1.5:1) to afford 16.1 mg of yellow oily water as the title compound (yield 25.4%). [α]D20 +13.3° (c=1.56, ethanol)
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][CH:10]=[C:11]([CH2:12]N(C)C)[C:5]=2[CH:4]=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[Na].Cl>>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([CH2:12][C:11]1[C:5]2[C:6](=[CH:7][CH:8]=[C:3]([CH2:2][CH3:1])[CH:4]=2)[NH:9][CH:10]=1)[C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH3:22]
Reactant: CCc1ccc2[nH]cc(CN(C)C)c2c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na]
Product: CCOC(=O)C(Cc1c[nH]c2ccc(CC)cc12)C(=O)OCC
Temperature: 120 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
The 5-Ethylgramine (1.25 g, 6.18 mmol) was combined with diethyl malonate (2.85 mL, 18.54 mmol) and heated to 120° C. until a homogeneous solution was formed. To this mixture was added sodium metal (100 mg, 4.36 mmol) and the mixture was stirred at 120° C. for 24 hours. TLC indicated the completion of the reaction. The reaction was allowed to cool to room temperature and a solution of 5% HCl (aqueous) was slowly added to the mixture and the resulting product was extracted with EtOAc. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulafate, filtered and evaporated to give compound 12 as a white solid (1.67 g; 85% yield; M+1=318.4). The product was taken into the next step without purification.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>CC#N>[O:16]1[CH2:17][CH2:18][CH:13]([O:12][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([NH:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]2)[N:11]=[CH:10]3)[CH2:14][CH2:15]1
Reactant: Clc1ncc2cccc(OC3CCOCC3)c2n1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O[C@H]1CC[C@H](Nc2ncc3cccc(OC4CCOCC4)c3n2)CC1

Procedure:
2-chloro-8-(tetrahydro-2H-pyran-4-yloxy)quinazoline (1 g, 3.8 mmol), trans-4-amino-cyclohexanol (0.524 g, 4.56 mmol) and DBU (0.69 g, 4.56 mmol) were suspended in MeCN (10 mL). The mixture was heated at reflux for 10 h. TLC showed the reaction was complete. The mixture was concentrated in vacuo, the residue was purified by HPLC to yield the title compound (0.373 g, 28%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 10.817 (d, 1H), 9.120 (s, 1H), 7.351 (m, 2H), 7.210 (m, 1H), 4.630 (m, 1H), 4.118 (m, 1H), 4.041 (m, 2H), 3.712 (m, 1H), 3.524 (m, 2H), 2.001 (m, 8H), 1.620 (q, 2H), 1.419 (q, 2H)
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:48][C@@H:49]([CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:50]1[CH:55]=[CH:54][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:52][CH:51]=1>CN(C=O)C>[CH:62]1([C@H:49]([NH:48][C:8]([C:7]2[C:2]([OH:1])=[N:3][C:4]([N:11]3[CH:15]=[CH:14][CH:13]=[N:12]3)=[N:5][CH:6]=2)=[O:10])[C:50]2[CH:51]=[CH:52][C:53]([P:56]([CH3:61])(=[O:60])[O:57][CH2:58][CH3:59])=[CH:54][CH:55]=2)[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1
Reactant: CCOP(C)(=O)c1ccc([C@@H](N)C2CCCCC2)cc1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1ccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.1 %

Procedure:
To a stirred solution of 8-b (2.6 g, 12.6 mmol) and Et3N (3.8 g, 37.8 mmol) in DMF (50 mL) was added HATU (5.8 g, 15.2 mmol). The mixture was stirred for 5 min at room temperature and then ethyl 4-((S)-amino(cyclohexyl)methyl)phenyl(methyl)phosphinate hydrochloride, 27-d, (4.2 g, 12.6 mmol) was added. The resulting mixture was stirred at room temperature for 15 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with 1N HCl. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel chromatography (ethyl acetate:MeOH=10/1) to provide the product, 27-e, (3.3 g, 54.1%).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([S:14]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N[C@H](CO)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(O)[C@@H](CO)NS(=O)(=O)c1ccccc1

Procedure:
In analogy to example 2, D-serine was reacted with benzenesulfonyl chloride to give (R)-2-benzenesulfonylamino-3-hydroxy-propionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([OH:7])[CH:13]=[CH2:14])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: C=C[Mg]Br
Reactant: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
To a solution of 3,4-dimethoxybenzaldehyde (5.30 g, 31.9 mmol) in THF (50 mL) was added dropwise under a nitrogen atmosphere at 0° C. over a period of 30 min vinylmagnesium bromide (1 M in THF, 32 mL, 32 mmol) and stirred for 2 h at 0° C. followed by 1 h at ambient temperature. Further vinylmagnesium bromide (1 M in THF, 32 mL, 32 mmol) was added at 0° C. and the solution was stirred for 1 h at this temperature. The reaction mixture was added onto a mixture of ice (50 g) and aqueous ammonium chloride (saturated, 50 mL). The mixture was extracted with tert-butylmethylether and the organic layers were washed with water (50 mL) and brine (50 mL). Drying over sodium sulfate und purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (5.18 g, 84%) as a light yellow oil.
Reaction SMILES: CC(C)([O-])C.[Na+].[O:7]1[C:11]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.Br[C:18]1[CH:19]=[CH:20][C:21]([Cl:26])=[C:22]([O:24][CH3:25])[CH:23]=1>CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd].C1(C)C=CC=CC=1.CC(O)(C)C>[Cl:26][C:21]1[CH:20]=[CH:19][C:18]([N:14]2[CH2:15][CH2:16][C:11]3([O:10][CH2:9][CH2:8][O:7]3)[CH2:12][CH2:13]2)=[CH:23][C:22]=1[O:24][CH3:25]
Reactant: COc1cc(Br)ccc1Cl
Reactant: C1CC2(CCN1)OCCO2
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1cc(N2CCC3(CC2)OCCO3)ccc1Cl
Temperature: 160 °C
Yield: 69.3 %

Procedure:
A 20-mL microwave vial was charged with sodium tert-butoxide (537 mg, 5.59 mmol), acetato(2′-di-t-butylphosphino-1,1′-biphenyl-2-yl)palladium (II) (259 mg, 0.559 mmol) and a stir bar. The vial was sealed and purged with nitrogen. A solution of 1,4-dioxa-8-azaspiro[4.5]decane (800 mg, 5.59 mmol) and 5-bromo-2-chloroanisole (1361 mg, 6.15 mmol) in 5:1 toluene/t-BuOH (12 mL) was added via syringe. The mixture was heated by microwave (300 W) at 160° C. for 10 min and then cooled and partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc and the organic phases were combined. The resultant solution was dried (Na2SO4) and concentrated on a rotary evaporator to give the crude product. The crude product was purified by flash chromatography using a 40 g silica gel cartridge column and gradient elution with EtOAc/hexanes to afford 8-(4-chloro-3-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.1 g, 70%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[OH:15].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.Cl.Cl[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=1[O-:64].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[N:9]=[C:10]1[NH:14][CH2:13][CH2:12][N:11]1[O:15][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N+:59]=1[O-:64]
Reactant: ON1CCNC1=Nc1c(Cl)cccc1Cl
Reactant: [O-][n+]1ccccc1CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: [O-][n+]1ccccc1CON1CCNC1=Nc1c(Cl)cccc1Cl
Reaction time: 2 h

Procedure:
A suspension of 9.84 g of 2-[(2,6-dichlorophenyl)imino]-1-hydroxyimidazolidine, 1.4 g of tetra-n-butylammonium sulfate and 7.56 g of 2-chloromethyl-pyridine N-oxide hydrochloride in 140 ml of toluene is treated with 30 ml of 28 percent sodium hydroxide while stirring vigorously. The temperature rises immediately to 30°. After 2 hours, the precipitate is removed by filtration under suction, washed with water and dried at 60° in vacuo. From methanol and acetonitrile there is obtained 2-([{2-[(2,6-dichlorophenyl)imino]-1-imidazol idinyl}oxy]methyl)-pyridine 1-oxide of melting point 185°-187°. The corresponding hydrochloride crystallizes from methanol/acetonitrile with 2.5 mol of hydrochloric acid and melts at 171°-173°. The corresponding cyclohexylsulfamate decomposes slowly from 159°-238°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:18])=O>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([Cl:15])[C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 99.3 %

Procedure:
A mixture of 20.4 g of 2,6-dichloro-4-trifluoromethylbenzoic acid (11), 18.8 g of thionyl chloride and a small amount of anhydrous N,N-dimethylformamide was stirred at 90° C. overnight. The thionyl chloride was distilled off, and the resulting residue was distilled under reduced pressure to obtain 21.7 g of the desired compound in the form of a colorless liquid (quantitative yield).
Reaction SMILES: [I:1][C:2]#[C:3][C:4]([CH3:7])([OH:6])[CH3:5].[F:8][C:9]([F:21])([F:20])[C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[CH2:13][N:14]=[N+:15]=[N-:16]>>[I:1][C:2]1[N:14]([CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([C:9]([F:8])([F:21])[F:20])[CH:11]=2)[N:15]=[N:16][C:3]=1[C:4]([OH:6])([CH3:7])[CH3:5]
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Reactant: CC(C)(O)C#CI
Product: CC(C)(O)c1nnn(Cc2cccc(C(F)(F)F)c2)c1I

Procedure:
Synthesized from 4-iodo-2-methylbut-3-yn-2-ol and 3-trifluoromethyl-benzylazide using general procedure; 3.82 g, 9.30 mmol, 93%; mp=77-80° C.; IR (υ[cm−1]) 3385, 2981, 2938, 1326, 1170, 1120, 1074, 763, 699; 1H NMR (600 MHz, CDCl3) δ=7.58-7.57 (m, 2H), 7.48-7.45 (m, 1H), 7.42-7.41 (m, 1H), 5.62 (s, 2H), 1.66 (s, 6H); 13C NMR (151 MHz, CDCl3) δ=156.4, 135.4, 131.5 (q, J=33.2), 131.4, 129.8, 125.7 (q, J=3.7), 125.1 (q, J=3.8), 123.9 (q, J=272.4), 74.2, 69.7, 53.8, 30.1; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C13H14F3IN3O, 412.0128; found 412.0126.
Reaction SMILES: [CH3:1][C:2]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.CO.C([O-])=O.[NH4+:22]>[Pd].O>[NH2:22][CH:5]1[CH2:6][CH2:7][C:2]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:1])[CH2:3][CH2:4]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(=O)CC1
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: CC1(NC(=O)OC(C)(C)C)CCC(N)CC1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a mixture of tert-butyl (1-methyl-4-oxocyclohexyl)carbamate (4.00 g) and methanol (50 mL), ammonium formate (10.2 g) and water (5 mL) were added and stirred for 1 hour until they were completely dissolved. Then, 10% palladium on carbon (2.0 g) was added and stirred at room temperature for 65 hours. After insoluble materials were separated by filtration through celite, the solvent was distilled off, and chloroform was added to the resulting residue, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off to give tert-butyl (4-amino-1-methylcyclohexyl)carbamate (3.73 g) as a colorless syrup.
Reaction SMILES: [C:1]([N:4]([CH3:22])[N:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]#[N:21])=[CH:15][CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C.[Co](Cl)Cl>[C:1]([N:4]([CH3:22])[N:5]([C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CC#N)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)N(C)N(C(=O)OC(C)(C)C)c1ccc(CCN)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 2-acetyl-1-[4-(cyanomethyl)phenyl]-2-methylhydrazinecarboxylate (607 mg) and cobalt chloride (520 mg) were dissolved in methanol (20 ml), and sodium borohydride (757 mg) was added by small portions at 0° C. The reaction mixture was stirred at room temperature for 2.5 hr, and diluted with ethyl acetate (200 ml). The obtained diluted solution was passed through basic silica gel (100 g) and washed with ethyl acetate:methanol=10:1 (volume ratio). The filtrate was concentrated under reduced pressure to give tert-butyl 2-acetyl-1-[4-(2-aminoethyl)phenyl]-2-methylhydrazinecarboxylate as a colorless oil.