Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:22])[CH3:20])[C@H:15]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:14]2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:38]C(C)([O-])C.[Na+].CI.O>CN(C=O)C>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([CH3:38])[C:11]([N:13]2[CH2:18][CH2:17][C@@H:16]([N:19]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[O:22])[CH3:20])[C@H:15]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[CH2:14]2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(NC(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CC(=O)N1CCC(N(C)C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To a solution of the compound obtained in Example 459 (100 mg) in DMF (3 mL) was added sodium tert-butoxide (25.3 mg) at 0° C., and the mixture was stirred for 5 min. Then, methyl iodide (16.5 μL) was added, and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0→12% methanol/ethyl acetate) to give the title compound (55 mg, 54%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[S:29])[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28](=[S:29])[NH:1][C:2]2[CH:3]=[C:4]([NH:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(NC(=O)c2ccccc2)cc1N
Product: COc1ccc(NC(=O)c2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 81.1 %

Procedure:
Prepared according to the procedure described for Example 78 using N-(3-amino-4-methoxyphenyl)-benzamide from Example 21 (0.88 g, 3.62 mmol) and 3,5-dichlorophenyl isothiocyanate (0.739 g, 3.62 mmol). Filtration without trituration afforded the product (1.31 g); m.p. 194-195° C.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCCC(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Triethylamine (23.1 ml) and hexanoyl chloride (11.4 ml) were added dropwise to a methylene chloride solution (300 ml) of L-proline benzylester hydrochloride (20.00 g) under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was successively washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate, and brine, dried over magnesium sulfate, and concentrated to obtain 26.20 g of N-hexanoyl-L-proline benzyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20]([O:24][C:25](ON=C(C1C=CC=CC=1)C#N)=[O:26])([CH3:23])([CH3:22])[CH3:21]>O1CCOCC1>[C:20]([O:24][C:25]([N:10]1[CH2:9][CH2:8][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:12][CH2:11]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: CCOC(=O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
1-(Ethoxycarbonylmethyl)-piperazine (5.00 g, 29.0 mmol) is dissolved in 35 mL of 50% aqueous dioxane. Triethylamine (4.41 g, 43.5 mmol) is added followed by 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (7.86 g, 31.9 mmol). The reaction is stirred for 14.5 hours at ambient temperature, then poured onto water and extracted with ethyl acetate (2×100 mL). The combined organic extracts are washed with water (3×100 mL), brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue is purified via silica gel chromatography with gradient elution (20%→50% ethyl acetate in hexanes) affording the desired product as an oil. CIMS: MH+ 273.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.Cl.[NH:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1>CN(C=O)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:18]2[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]2)=[CH:11][CH:10]=1
Reactant: O=S1(=O)CCNCC1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)CCN(Cc2ccc(Br)cc2)CC1
Reaction time: 3 h

Procedure:
2.18 ml (15.5 mmol) of triethylamine are added to a colorless suspension of 1.28 g (5 mmol) of 4-bromobenzyl bromide and 944 mg (5.5 mmol) thiomorpholine-1,1-dioxide hydrochloride in 15 ml DMF. After 3 h at RT, the reaction mixture is partitioned between CH2Cl2 and H2O. The aqueous phase is re-extracted four times with CH2Cl2. The combined organic extracts are washed with water, saturated brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo to afford, after drying in HV, the title compound which is used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:16])[C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[F:16][C:11]1[C:10]([CH3:17])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH2:15]
Reactant: Cc1c(Oc2ccnc(Cl)c2)ccc(N)c1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(Oc2ccnc(-c3cnn(C)c3)c2)ccc(N)c1F
Yield: 75.2 %

Procedure:
4-(2-Chloropyridin-4-yloxy)-2-fluoro-3-methylbenzenamine (1.0 g, 3.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.8 mmol), Na2CO3 (0.84 g, 6.6 mmol) and Pd(PPh3)4 (0.25 g, 0.2 mmol) were combined in DME (75 mL) and water (25 mL). The mixture was sparged with nitrogen for 15 min and was heated to reflux overnight. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organics were washed with brine, concentrated in vacuo and purified by silica gel chromatography to give 2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (0.74 g, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=6.0 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.63 (m, 2H), 6.45 (dd, J=5.6, 2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 299.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH:32]=O)=[CH:24]2)=[CH:20][CH:19]=1>CO>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([CH:32]=[C:7]3[C:6]4[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:16]=[CH:15][C:14]=4[C:13]4[C:8]3=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:24]2)=[CH:34][CH:35]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)c2ccccc12
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(=Cc1cn(Cc3ccc(Cl)cc3)c3ccccc13)c1ccccc1-2
Temperature: 85 °C
Reaction time: 18 h

Procedure:
To a solution of 2-nitrofluorene (250 mg, 1.18 mmol) in 20 mL of methanol was added 1-(4-Chloro-benzyl)-1H-indole-3-carbaldehyde (382 mg, 1.42 mmol) and KF—Al2O3 (189 mg, 1.18 mmol). The resulting mixture was stirred at 85° C. for 18 hrs. After that, TLC showed that 2-nitrofluorene was gone, and many solids were suspended in MeOH. 260 mg of CYD-2-21 was obtained as a yellow solid after filtration and recrystallization from CH2Cl2. One isomer: 1H-NMR (600 MHz, d6-DMSO) δ 8.96 (s, 1H), 8.41 (s, 1H), 8.27 (m, 2H), 8.18 (m, 3H), 8.09 (d, 1H, J=7.2 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz), 7.47 (m, 5H), 7.28 (t, 1H, J=7.2 Hz), 7.20 (t, 1H, J=7.2 Hz), 5.57 (s, 2H). Another isomer: 1H-NMR (600 MHz, d6-DMSO) δ 9.01 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.19 (m, 4H), 7.86 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz), 7.47 (m, 5H), 7.28 (t, 1H, J=7.2 Hz), 7.20 (t, 1H, J=7.2 Hz), 5.59 (s, 2H). 13C-NMR (150 MHz, d6-DMSO) δ 147.1, 146.6, 145.6, 142.9, 141.9, 141.0, 138.2, 138.0, 137.0, 136.8, 136.7, 136.4 (2C), 135.6, 132.7, 132.2, 132.1, 130.2, 129.9, 129.8, 129.7, 129.2, 129.1, 129.0 (2C), 128.4, 128.1 (2C), 127.9, 124.5, 124.1, 123.8, 123.2 (2C), 123.1, 122.4, 122.0, 121.7, 121.2, 121.0 (2C), 120.8, 120.6 (2C), 120.2, 118.8, 118.7, 116.2 (2C), 111.5, 111.4, 111.3 (2C), 49.4, 49.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12].[H][H]>C(O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: OCCCC#Cc1ccccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: OCCCCCc1ccccn1
Yield: 93.1 %

Procedure:
5-(2-pyridinyl)-4-pentyn-1-ol (8.8 g) was hydrogenated over 1.0 g of 10% Pd/C in 125 mL of ethanol at room temperature and atmospheric pressure. After the uptake of hydrogen had stopped, the catalyst was removed by filtration and the solvent was removed under reduced pressure. The residual oil was distilled on a Kugelrohr apparatus (115°-120° C./0.1 mm) to yield 8.4 g of 2-pyridinepentanol.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH:22]1([NH2:26])[CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:26][C:18]([C:14]2[S:13][C:12](/[CH:11]=[CH:10]/[C:9]3[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=3[CH3:21])=[N:16][C:15]=2[CH3:17])=[O:20])[CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCC1
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC2CCC2)s1
Yield: 15 %

Procedure:
As described for example 108, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (400 mg, 1.3 mmol) was converted, using cyclobutylamine instead of 3,3-difluoroazetidine hydrochloride, to the title compound (68 mg, 15%) which was obtained as a white solid. MS: m/e=360.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][NH:17][C:18](OC3C=CC([N+]([O-])=O)=CC=3)=[O:19])[O:14][CH2:13][CH2:12][N:11]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:38][O:39][C:40](=[O:44])[CH2:41][NH:42][CH3:43].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@@H:15]([CH2:16][NH:17][C:18](=[O:19])[N:42]([CH2:41][C:40]([O:39][CH3:38])=[O:44])[CH3:43])[O:14][CH2:13][CH2:12][N:11]([C:30]([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNC(=O)Oc2ccc([N+](=O)[O-])cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: CNCC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CN(C)C(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-({[(4-nitrophenoxy)carbonyl]amino}methyl)-1,4-oxazepane-4-carboxylate (94 mg) in THF (2.0 mL) were added sarcosine methyl ester hydrochloride (36 mg) and potassium carbonate (72 mg), and the mixture was stirred at room temperature overnight. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (79 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH2:13]([CH:15]1[O:17][CH2:16]1)[Cl:14]>CCOCC>[CH2:1]([O:8][CH2:16][CH:15]([OH:17])[CH2:13][Cl:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Product: OC(CCl)COCc1ccccc1
Temperature: 80 °C
Yield: 58.6 %

Procedure:
A 1,000 mL, 3-necked flask equipped with a mechanical stirrer, condenser, thermometer and 500 mL addition funnel was charged with benzyl alcohol (324 g, 3.0 mol) and 5% BF3 -etherate in ether (10 mL). This mixture was stirred and heated to 80° C. Epichlorohydrin (278 g, 3.0 mol) was added dropwise over 6 hours, and the reaction mixture was stirred an additional 24 hours at 80° C. The crude product was distilled from NaHCO3 (1 g) using a 25 cm Vigreux column. The fractions boiling from 95° C. (0.05 mm) to 120° C. (0.03 mm) were collected and combined to yield 353 g (58%) of pure 3-benzyloxy-2-hydroxypropyl chloride.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:7][S:8]([C:11]1[S:15][C:14]([NH:16]C(=O)C)=[N:13][C:12]=1[CH3:20])(=[O:10])=[O:9])([CH2:5][OH:6])[CH3:4]>Cl>[OH:6][CH2:5][C:3]([NH:7][S:8]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:20])(=[O:10])=[O:9])([CH2:2][OH:1])[CH3:4]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)NC(C)(CO)CO)s1
Agent: Cl
Product: Cc1nc(N)sc1S(=O)(=O)NC(C)(CO)CO
Temperature: 80 °C
Yield: 38.3 %

Procedure:
A stirred suspension of 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (0.33 g, 1.02 mmol) in 6N hydrochloric acid (4 ml) was heated for 2 h at 80° C., evaporated., and saturated NaHCO3 solution (30 ml) was added. The mixture was extracted with ethyl acetate (3×50 ml), the combined organic layers washed with brine (30 ml) and dried (MgSO4). The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to yield the title compound (0.11 g, 38%) as a white solid. MS (ISP) 280.0 [(M−H)−]; mp 170° C.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[C:8]([O:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1cc(Oc2ccc(Cl)cc2Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To a solution of 4,5-dichloro-2-nitroaniline (20 g, 96.61 mmol) in DMSO (200 ml) was added 2,4-dichlorophenol (15.8 g, 96.93 mmol) and potassium carbonate (26.7 g, 193.18 mmol). The resulting solution was stirred overnight at 90° C. and then quenched by the addition of water (1000 ml). The resulting solution was extracted with ethyl acetate (3×500 ml) and the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to produce 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline as a yellow solid (23 g, 71%). Next, the 4-chloro-5-(2,4-dichlorophenoxy)-2-nitroaniline (22 g, 65.96 mmol) was added to ethanol (200 ml) and hydrogen chloride (16 ml, 197.9 mmol). This was followed by the addition of Zn powder (21.4 g, 395.8 mmol) at room temperature in portions. The resulting solution was stirred for 4 h at 85° C. and then concentrated under vacuum. The residue was dissolved in water (500 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with ethyl acetate (4×200 ml). The combined organic layers were dried and concentrated under reduce pressure to give a residue, which was purified by a silica gel column with 10%˜20% ethyl acetate in petroleum ether to afford 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine as a red oil (15 g, 75%). Finally, a solution of 4-chloro-5-(2,4-dichlorophenoxy)benzene-1,2-diamine (14 g, 46.12 mmol) in heptafluorobutanoic acid (150 ml) was stirred overnight at 80° C. in an oil bath. The reaction was then quenched by the addition of water (400 ml), adjusted pH value of the solution to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 2%˜10% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-dichlorophenoxy)-2-(heptafluoropropyl)-1H-1,3-benzodiazole as a white solid (10.4705 g, 47%).
Reaction SMILES: [Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.O.O[N:12]1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.N>CN(C=O)C>[Br:1][C:2]1[O:6][CH:5]=[C:4]([C:7]([NH2:12])=[O:9])[CH:3]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1coc(Br)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 78.9 %

Procedure:
A solution of 5-bromo-furan-3-carboxylic acid (0.364 g, 1.92 mmol), 3-hydroxybenzotriazole hydrate (0.28 g, 2.11 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.40 g, 2.11 mmol) in DMF (11 mL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to 0° C. and aq. NH3 (0.22 mL) is added. The mixture is stirred at room temperature for an additional 5 hours, then the solvent is removed in vacuo and the residue dissolved in EtOAc, washed with 1N NaOH, and 1N HCl. The organic layers are combined, dried over MgSO4 and concentrated to afford the title compound (0.288 g, 79%). HPLC (254 nm): Rt 2.17 min (85.3%).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(C)(C)C.C([N:27]([C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:39]=1[CH:40]=O)C(=O)C(C)(C)C)=O.[OH-].[Na+]>C(O)C>[C:16]1([C:15]2[C:14]([C:11]3[CH:10]=[CH:9][C:8]([CH2:7][OH:6])=[CH:13][CH:12]=3)=[N:27][C:34]3[C:39]([CH:40]=2)=[CH:38][CH:37]=[N:36][CH:35]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)C(=O)N(C=O)c1cnccc1C=O
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ccc(-c2nc3cnccc3cc2-c2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a partial suspension of 1-[4-({[t-butyl-(dimethyl)silyl]oxy}methyl)phenyl]-2-phenylethanone (1.03 gm, 3.0 mmol) and N-formyl-N-(4-formylpyridine-3-yl)-2,2-dimethylpropanamide (704 mg, 3.0 mmol) in absolute ethanol (8 mL) was added dropwise 5N NaOH (2.5 mL, 12.5 mmol). This mixture was heated at 70° C. over night. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and aqueous sodium carbonate. The organic layer was dried (Na2SO4), the solution filtered, and the solvent evaporated. This residue was chromatographed on a column of silica gel eluting with 40-100% ethyl acetate/hexane and then 0.5-1.5% methanol/ethyl acetate (sat'd with ammonia). The appropriate fractions were combined and the solvents evaporated. The residue was triturated with diethyl ether to give crystalline title compound. 1H-NMR (500 MHz, CDCl3): δ 9.60 (1H, s), 8.65 (1H, d, J=5.5 Hz), 8.17 (1H, s), 7.71 (1H, d, J=5.6 Hz), 7.48 (2H, d, J=6.5 Hz), 7.25-7.36 (7H, m), 4.72 (2H, s). m/e (m+1): 313.2.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[C@@:21]12(O)[N:28](C)[C@@H:25]([CH2:26][CH2:27]1)[CH2:24][CH:23]=[CH:22]2>>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:20][CH:19]=2)([OH:11])[C:7]([O:9][C@@:10]23[N:28]([CH3:21])[C@@H:25]([CH2:26][CH2:27]2)[CH2:24][CH:23]=[CH:22]3)=[O:8])=[CH:17][CH:16]=1
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: COC(=O)C(O)(c1ccc(C)cc1)c1ccc(C)cc1
Product: Cc1ccc(C(O)(C(=O)O[C@]23C=CC[C@H](CC2)N3C)c2ccc(C)cc2)cc1

Procedure:
4.10 is prepared analogously to the method according to II.1. Yield: 3.55 g (81% of theory) starting from 2.87 g (0.01 mol) of 3e and 1.48 g (0.01 mol) of tropenol; to purify it, the hydrochloride was precipitated and recrystallized from acetonitrile. Melting point: 232° C.-233° C. (hydrochloride).
Reaction SMILES: C([O-])(=O)COCC([O-])=O.[Zn+2:10].[C:11]([OH:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17].C(O)(=O)COCC(O)=O>>[C:11]([O-:20])(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O-:18])=[O:17].[Zn+2:10]
Reactant: O=C(O)CCCCC(=O)O
Agent: O=C(O)COCC(=O)O
Agent: O=C([O-])COCC(=O)[O-]
Agent: [Zn+2]
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
Zinc adipate was prepared by essentially the procedure described above for zinc diglycolate, with the exception that adipic acid (14.65 g, 0.1 mole, Fisher Scientific, Hampton, N.H.) was substituted for the diglycolic acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)OC(C)(C)C)[C:5]([CH:16]=[N:17][OH:18])=[CH:4][CH:3]=1>Cl.O1CCOCC1>[ClH:1].[NH2:8][C:6]1[C:5]([CH:16]=[N:17][OH:18])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C=NO
Agent: Cl
Solvent: C1COCCO1
Product: Nc1nc(Cl)ccc1C=NO
Reaction time: 0.5 h

Procedure:
15.5 g (57 mmol) of tert-butyl {6-chloro-3-[(hydroxyimino)methyl]pyridin-2-yl}carbamate (Example 107A) are dissolved in 285 ml of 4N hydrogen chloride in dioxane and stirred for 30 min. The reaction mixture is concentrated to one half, and an equal portion of diethyl ether is added. The reaction mixture is stirred for 20 min and the product is filtered off and washed with diethyl ether. 11 g (94% of theory) of the product are obtained as a solid.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(#N)C>[NH2:1][C@H:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[CH2:5]1
Reactant: [N-]=[N+]=N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (3S)-3-azido-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (3.43 g, 11.6 mmol) (obtained as described in Reference Example 52(3)) in acetonitrile (103 ml) was added triphenylphosphine (3.19 g, 12.2 mmol), and the mixture was stirred in an oil bath (70° C.) for 2 hours. After checking the completion of the reaction, sodium sulfate decahydrate (3.93 g, 12.2 mmol) was added thereto and the reaction mixture was stirred for 5 hours. After checking the completion of the reaction, the reaction mixture was filtered and partitioned between methylene chloride and 0.1M aqueous hydrogen chloride solution. To the obtained aqueous layer were added methylene chloride and sodium hydrogencarbonate, and the aqueous layer was extracted with methylene chloride. The obtained organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dried under reduced pressure to give (3S)-3-amino-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (2.83 g, yield 92%) as a pale yellow solid.