Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([O:36][CH:37]([F:39])[F:38])=[CH:31][C:30]=1[F:40].O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH2:28][C:29]3[C:30]([F:40])=[CH:31][C:32]([O:36][CH:37]([F:38])[F:39])=[CH:33][C:34]=3[F:35])[N:7]=[C:6]([C:9]3[N:14]=[C:13]([NH:15][C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[C:12]([O:22][CH3:23])=[CH:11][N:10]=3)[C:5]=2[CH3:24])[CH2:3][CH2:2]1
Reactant: Fc1cc(OC(F)F)cc(F)c1CBr
Reactant: COc1cnc(-c2n[nH]c(C3CC3)c2C)nc1Nc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cnc(-c2nn(Cc3c(F)cc(OC(F)F)cc3F)c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
70 mg 2-(5-cyclopropyl-4-methyl-1H-pyrazol-3-yl)-5-methoxy-N-(pyridin-4-yl)pyrimidin-4-amine 1-16-1 (0-217 mmol, 1.0 eq) were dissolved in 0.52 mL THF and cooled to 0° C. 10.4 mg sodiumhydride (60%, 0.261 mmol, 1.2 eq) were added. The mixture stirred for 5 minutes, then the ice bath was removed and 65.2 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.239 mmol, 1.1 eq) were added. The reaction stirred at rt for 4 days. Again 5 mg sodiumhydride (60%, 0.130 mmol, 0.6 eq) and 33 mg 2-(bromomethyl)-5-(difluoromethoxy)-1,3-difluorobenzene (0.120 mmol, 0.55 eq) were added. The reaction stirred at rt for 2 hours. Water was added and the aqueous layer was extracted by ethylacetate twice. The collected organic layers were washed with brine, dried with a silicon filter and concentrated in vacuo The crude product was purified by flashcromatography and HPLC to provide 10 mg (0.02 mmol, 8%) of the analytically pure target compound.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:9][O:10][C:11]([C:13]1[CH:14]=[N:15][C:16](Cl)=[C:17]([Br:19])[CH:18]=1)=[O:12]>CN(C=O)C>[CH3:9][O:10][C:11]([C:13]1[CH:14]=[N:15][C:16]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]([Br:19])[CH:18]=1)=[O:12]
Reactant: OC1CCCC1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(OC2CCCC2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
Cyclopentanol (1 mL, 11 mmol) was dissolved in DMF (25 mL) and a dispersion of sodium hydride in oil (55-65%, 480 mg) was added at room temperature. The mixture was stirred for 1 h at room temperature and 5-bromo-6-chloro-3-pyridinecarboxylic acid methyl ester (2.5 g, 10 mmol) was added. Stirring was continued for 1 h at room temperature and the mixture was afterwards partitioned between water and diethyl ether. Organic phases were pooled, dried with MgSO4 and the solvent was evaporated. The residue was purified by column chromatography on silica (n-heptane/ethyl acetate 9:1) to yield 0.48 g of the title compound as a colorless oil, MS (EI) 299.0, 301.0 (M)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:9][CH2:8][NH:7]1)=[O:5].C([O-])(O)=O.[Na+].[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>C1COCC1.O.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]2[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=2)[CH2:9][CH2:8][N:7]1[C:25](=[O:26])[C:24]([CH3:29])([CH3:28])[CH3:23])=[O:5]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)[C@H]1NCC[C@@H]1c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@@H]1[C@@H](c2ccc(O)cc2)CCN1C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 137.9 %

Procedure:
To the solution of (2S,3R)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid methyl ester hydrochloride (200 mg, 0.76 mmol), prepared in Example 20, in THF/H2O (2 mL/1 mL) was added saturated NaHCO3 (5 mL). To the above mixture was added trimethylacetyl chloride (420 mg, 3.5 mmol) over 20 min. The resulting solution was then stirred at room temperature for 4 hours and was diluted with ethyl acetate to 30 mL. The organic layer was then washed with brine (2×5 mL) and was concentrated to give (2S,3R)-1-(1-oxo-2,2,2-trimethylethyl)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid methyl ester as a white solid (320 mg). This solid was dissolved in 3 mL of EtOH and was stirred with 1N sodium hydroxide (3 mL, 3 mmol) at room temperature for 8 hours. After acidification with 6N HCl, the solvent was removed and the residue was extracted with dichloromethane. After concentration, the residue was washed ether to give (2S,3R)-1-(2,2-dimethyl-1-oxopropyl)-3-(4-hydroxyphenyl)pyrolidine-2-carboxylic acid as a white solid (117 mg). HRMS (M+H): Obs. 292.1556, Cald. 292.1549.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.Cl.[C:12]([O:16][C:17](=[O:21])[CH2:18][NH:19][CH3:20])([CH3:15])([CH3:14])[CH3:13].[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:20][N:19]([CH3:22])[CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])=[CH:4][CH:5]=1)#[N:10]
Reactant: O=C([O-])[O-]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of alpha-bromo-p-tolunitrile (10.0 g, 51 mmol), sarcosine tert-butyl ester hydrochloride (10.2 g, 56 mmol) and potassium carbonate (21.2 g, 153 mmol) in acetone (100 mL) was stirred at 60° C. overnight. Resulting suspension was filtered off and salts were washed with acetone (2×150 mL). The filtrate was concentrated under reduced pressure. The residue was diluted with water (200 mL) and extracted with EtOAc (2×150 mL). The combined organic layers were washed with water (200 mL), dried (MgSO4) and the solvents were removed under reduced pressure to give the title compound as a yellow oil used without further purification (11.7 g, 88%). 1H NMR (DMSO-d6, 300 MHz) δ 7.79 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 3.71 (s, 2H), 3.20 (s, 2H), 2.23 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 260.9 (M+H)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[N:28]=[C:27]([CH3:29])[N:26]=[C:25]([NH2:30])[N:24]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[N:24]=[C:25]([NH2:30])[N:26]=[C:27]([CH3:29])[N:28]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccc(F)cc3n2-c2ccccc2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (100 mg, 0.31 mmol), 4-chloro-6-methyl-[1,3,5]triazin-2-ylamine (48.4 mg, 0.34 mmol) and DIPEA (0.26 mL, 1.52 mmol) in n-butanol (2 mL) was stirred at 90° C. in a sealed vial for 16 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (C18, gradient 20-45% MeOH in 0.5% TFA/H2O) then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH affording 258 as a white solid (94.2 mg, 85%). LCMS (Method K): RT 3.04 min [M+H]+ 364.1. 1H NMR (DMSO-d6, 400 MHz, 80° C.): δ 7.65 (1H, dd, J=8.7, 4.8 Hz), 7.61-7.57 (2H, m), 7.55-7.51 (3H, m), 7.04 (1H, ddd, J=9.8, 8.7, 2.5 Hz), 6.91 (1H, bs), 6.77 (1H, dd, J=9.0, 2.5 Hz), 6.13 (2H, bs), 5.26 (1H, quintet, J=7.3 Hz), 2.02 (3H, s), 1.44 (3H, d, J=6.9 Hz)
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H][H].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CS(C)=O.O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1
Reactant: NCCCNc1ccccn1
Reactant: [H][H]
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN(CCCN)c2ccccn2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A mixture of sodium hydride (0.95 g) and 2-(3-aminopropylamino) pyridine (5.4 g) in DMSO (25 ml) was heated slowly to 85° C. under nitrogen. After the evolution of hydrogen had ceased the solution was cooled to room temperature and 4-methoxybenzyl chloride (5.59 g) in DMSO (5 ml) added dropwise keeping the temperature below 30° C. After a further 1 hr, water (300 ml) was added and the mixture extracted with ether. The extract was washed with 2N hydrochloric acid. The pH of the acid washings was adjusted to 4-5. After extracting with chloroform the pH was raised to 14 and extracted with ether. The ether extract was washed with water, dried (K2CO3) and stripped to give 2-[N-(3-aminopropyl)-N-(4-methoxybenzyl)-amino]pyridine (7.19 g) as an oil which was used without further purification. (ii) 2-[N-(3-aminopropyl)-N-(4-methoxybenzyl)amino]pyridine (1.0 g) and 2-nitroamino-5-(6-methylpyrid-3 -ylmethyl)pyrimid-4-one (0.8 g) were heated together under reflux in pyridine (10 ml) for 20 hr. On cooling, the mixture was stripped, the residue triturated with ether and recrystallised twice from ethanol/water to give 2-[3-[N-(4-methoxybenzyl)-N-pyrid-2-ylamino]propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one 1H2O, 0.72 g (48%), mp 90°-98° C. (softens).
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>CN(C)C=O>[CH2:23]([O:22][C:20]([C:19]1[N:1]=[C:2]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[S:3][CH:18]=1)=[O:21])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 8 h
Yield: 70.8 %

Procedure:
tert-Butyl 4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate (May-bridge) (85 mmol; 20.8 g) is dissolved in 250 ml of dimethylformamide and placed at 5° C. Ethyl bromopyruvate (1 eq.; 85 mmol; 16.6 g) dissolved in 50 ml of dimethylformamide is added dropwise. The reaction medium is stirred overnight and excess triethylamine is then added dropwise. The reaction medium is evaporated and the residual brown oil is taken up in ethyl acetate and washed with water (twice) and then with saturated sodium chloride solution (twice). The organic phase is dried over sodium sulfate and evaporated to dryness. The crude product is chromatographed on silica, eluting with dichloromethane to dichloromethane/3% methanol, to give 20.5 g of the expected product in the form of oily crystals. TLC: 1/1 ethyl acetate/hexane: Rf=0.55
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]2)=[CH:4][C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:26])[F:25].[CH:37](OCC)=[CH2:38]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:19][CH:37]=[CH2:38])[C:9]2([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:10][CH2:11]2)=[CH:4][C:3]=1[NH:20][C:21](=[O:36])[C@H:22]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@@H:23]([CH3:28])[C:24]([F:27])([F:25])[F:26]
Reactant: C=COCC
Reactant: C[C@H]([C@H](C(=O)Nc1cc(C(O)C2(C(=O)OC(C)(C)C)CC2)ccc1Cl)c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClCCl
Product: C=COC(c1ccc(Cl)c(NC(=O)[C@H](c2ccc(Cl)cc2)[C@@H](C)C(F)(F)F)c1)C1(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
Under argon, 473 mg (0.87 mmol) of tert-butyl 1-[(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)(hydroxy)methyl]cyclopropanecarboxylate (as diastereomer mixture) were dissolved in 2.4 ml of dichloromethane, and 1.24 ml (13 mmol) of ethyl vinyl ether and 11 mg (0.03 mmol) of)bis(acetato)(1,10-phenanthrolin-N1,N10)palladium [J. Org. Chem. 62, 1560-1562 (1997)] were added at room temperature. The reaction solution was then heated to 50° C. and stirred at this temperature for two days. Another 1.24 ml (13 mmol) of ethyl vinyl ether and 11 mg (0.03 mmol) of)bis(acetato)(1,10-phenanthrolin-N1,N10)palladium were then added, and stirring of the reaction mixture was continued at 50° C. overnight. This procedure was repeated two more times. The reaction solution was then cooled to room temperature and concentrated to dryness under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/dichloromethane 1:1). This gave 298 mg of the target compound (60% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:21]=[CH:22][C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25](=[O:33])(=[O:32])[C:24]=2[CH:34]=1>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:30]1[CH:29]=[CH:28][C:27]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:34][C:24]=3[S:25](=[O:32])(=[O:33])[C:26]=2[CH:31]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S1(=O)c2ccccc2-c2ccc(I)cc21
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)c1ccccc1-2

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) 3-iododibenzo[b,d]thiophene 5,5-dioxide (Intermediate 232), the title compound was obtained as a pink solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]([CH3:14])[C:8]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+].[C:23]1([P:29]([O:33]CC)[O:30][CH2:31][CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(#N)C>CCOC(C)=O>[CH3:14][C:9]1[CH:10]=[CH:11][C:12]([CH3:13])=[CH:7][C:8]=1[P:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:33])[O:30][CH2:31][CH3:32]
Reactant: Cc1ccc(C)c([Si](C)(C)C)c1OS(=O)(=O)C(F)(F)F
Reactant: CCOP(OCC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOP(=O)(c1ccccc1)c1cc(C)ccc1C

Procedure:
3,6-dimethyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate (25 mg, 0.077 mmol), Cesium Fluoride (64 mg, 0.421 mmol), Diethyl phenylphosphonite (60 mg, 0.306 mmol), Acetonitrile (1 ml): Reaction Time: 32 h; Rf: 0.4 (1:1 EtOAc:Pet Ether); Thick oil; 13.0 mg, 62%; 1H NMR (400 MHz, CDCl3, TMS) δ 7.81-7.70 (m, 3H), 7.52-7.40 (m, 3H), 7.23 (d, J=7.8 Hz, 1H), 7.12-7.05 (m, 1H), 4.11 (apparent quint, J=7.0 Hz, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 1.38 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 138.6 (d, J=10.8 Hz), 135.0 (d, J=12.3 Hz), 133.9 (d, J=9.3 Hz), 132.5 (d, J=124.1 Hz), 128.4 (d, J=13.4 Hz), 131.7, 131.5 (d, J=7.7 Hz), 131.4, 131.3, 129.0 (d, J=133.3 Hz), 128.4 (d, J=13.1 Hz), 60.7 (d, J=5.4 Hz), 20.9, 20.7 (d, J=3.9 Hz), 16.4 (d, J=6.9 Hz); 31P NMR (162 MHz, CDCl3,) δ 32.2; HRMS-ESI (m/z) calcd (C16H19O2P+H)+: 275.1195. found: 275.1193.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[N:10]([CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[C:11](=[O:25])[CH:12]([CH3:24])[N:13]1C(=O)C2C(=CC=CC=2)C1=O.CN.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CN(C)C=O.O>[ClH:1].[ClH:1].[NH2:13][CH:12]([CH3:24])[C:11]([N:10]([C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH2:26][CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:25]
Reactant: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)C(C)N1C(=O)c2ccccc2C1=O
Agent: CN
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1N(CCCc1cccnc1)C(=O)C(C)N
Reaction time: 8 h
Yield: 128.5 %

Procedure:
To a solution of 45.0 g of rac-2,3-dihydro-N-(2,6-dimethylphenyl)-alpha-methyl-1,3-dioxo-N-[3-(3-pyridinyl) -propyl]-1H-isoindole-2-acetamide hydrochloride dissolved in 200 ml of dimethylformamide was added 100 ml of 40% aqueous methylamine. The reaction mixture was stirred overnight, diluted with water, and extracted twice with dichloromethane. The combined organic layers were washed with water, dried with potassium carbonate, and evaporated to give an oil. The oil was converted to the dihydrochloride salt and crystallized from methanol ether to give 23.25 g of rac.-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridinyl) -propyl]propanamide dihydrochloride, mp 256°-260° C. The mother liquors afforded an additional 4.9 g, mp 256°-259° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].ClS([N:17]=[C:18]=[O:19])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:18]([NH2:17])=[O:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)sc1N
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)c1nc(C)sc1NC(N)=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.3 %

Procedure:
To a solution of 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (15.0 g, 0.081 mol) in DCM (550 mL) was added chlorosulfonyl isocyanate (8.92 mL, 0.102 mol) dropwise at −78° C. The thick suspension was allowed to warm to RT and stirred for 45 minutes. The resulting precipitate was collected by filtration and dried in vacuo. The resultant white solid was suspended in an aqueous solution of HCl (6 M, 400 mL) and heated at 90° C. for 1 h. The resulting solution was cooled to 0° C. and pH adjusted to 5 with an aqueous solution of NaOH (6 M). The resultant precipitate was collected by filtration and dried in vacuo at 60° C. for 36 h to give the title compound (16.4 g, 89%).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1.[Cl:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22]>CN(C=O)C>[Cl:18][CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][O:22][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:6]=1
Reactant: ClCc1cccc(Oc2ccccc2)n1
Reactant: CC(C)(CO)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CCl)COCc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 11.6 %

Procedure:
Under a nitrogen atmosphere, 0.65 g of sodium hydride (60% oily suspension) was suspended in 10 ml of dry DMF, and a solution of 3.23 g of 2-chloromethyl-6-phenoxypyridine and 2.00 g of 3-chloro-2,2-dimethylpropanol in 10 ml of dry DMF was added dropwise with ice-cooling. After stirring for 12 hours at room temperature, the reaction solution was poured into dilute hydrochloric acid-ice water and extracted twice with diethyl ether. The ether layers were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was subjected to column chromatography on silica gel (developing solvent, hexane:ethyl acetate=50:1) to obtain 0.52 g of desired 6-phenoxy-2-pyridylmethyl 3-chloro-2,2-dimethylpropyl ether [present compound (1)] as a colorless oily product.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8])=O.[OH-].[Li+].[NH3:11]>[H][H].[Pd]>[NH2:11][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][C:7]#[N:8].[NH2:11][CH2:1][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: [H][H]
Reactant: N
Reactant: N#CCCCCC=O
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Product: N#CCCCCCN
Product: NCCCCCCN
Temperature: 100 °C
Reaction time: 23 h
Yield: 59.01 %

Procedure:
In the autoclave described in Example 1 there were placed 20 g of 5-formylvaleronitrile and 3 g of Pd (2%) on Al2O3 powder and 0.41 g of lithium hydroxide under protective gas (argon). The autoclave was then sealed and 140 ml of NH3 were forced in. The mixture was stirred using a magnetic stirrer and was heated to 100° C. and the overall pressure raised to 80 bar by forcing in hydrogen and then kept at this value by continuous replenishment with hydrogen. After a period of 23 hours the autoclave was depressurized and the hydrogenation effluent analyzed by gas chromatography. The products formed comprised 59.01% of 6-aminocapronitrile and 5.1% of hexamethylene diamine (conversion 100%).
Reaction SMILES: C(O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[S:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1F)(=[O:14])(=[O:13])[NH2:12].Cl.CN([CH:26]=[O:27])C>>[O:27]([CH2:26][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:11](=[O:14])(=[O:13])[NH2:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccccc1F
Reactant: CN(C)C=O
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: NS(=O)(=O)c1ccccc1COc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
To a solution of benzyl alcohol (1 g, 8.6 mmol) in 10 mL of dry DMF was added to NaH (0.7 g, 17.1 mmol.) at 0° C. The reaction mixture was stirred at 0° C. for 30 min under N2. To the resulting mixture was added 2-sulfamoyl fluorobenzene (1 g, 5.7 mmol.) in 20 mL of dry DMF. The reaction mixture was stirred at 80-90° C. for 3 hours. After cooling to r.t., the reaction mixture was poured into ice-water and neutralized with aq. HCl (2 M) to pH 7. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was over Na2SO4, filtered and concentrated to afford crude 1-(phenoxymethyl)-2-sulfamoylbenzene (1 g, 66.7%), which was used directly without further purification.
Reaction SMILES: [C:1]1([S:7]([N:10]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[C:21]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)S(C2C=CC=CC=2)(=O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[OH-].[Na+]>CO>[CH3:25][C:22]1[C:21]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:20]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])[O:24][N:23]=1
Reactant: Cc1noc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c1-c1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2ccccc2)c1-c1ccccc1
Temperature: 45 °C
Reaction time: 0.33 h
Yield: 101.2 %

Procedure:
N-Benzenesulfonyl-N-(3-methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide (300 mg, 0.66 mmol) was dissolved in methanol. Potassium hydroxide (300 mg, 5.5 mmol) was added and the solution was warmed to 45° C. to dissolve the sodium hydroxide. Stirring was continued for 20 min. Methanol was removed under reduced pressure. The residue was dissolved in water, cooled to 0° C. and acidified to pH 3-4 with concentrated HCl. The solid precipitate was extracted with ethyl acetate, dried and evaporated in vacuo to give 210 mg (100% yield) of N-(3-methyl-4-phenyl-5-isoxazolyl)benzenesulfonamide, which was further purified by recrystallization from ethyl acetate/hexanes, m.p. 124°-126° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[C:15](/[CH3:25])=[CH:16]\[C:17](=[N:22]/[O:23][CH3:24])\[C:18]([O:20]C)=O)=[N:9]2)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:25])=[CH:16][C:17](=[N:22][O:23][CH3:24])[C:18]([NH:27][CH3:26])=[O:20])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CO/N=C(\C=C(\C)COc1ccn(-c2ccc(Cl)cc2)n1)C(=O)OC
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)C(C=C(C)COc1ccn(-c2ccc(Cl)cc2)n1)=NOC

Procedure:
0.68 g (1.87 mmol) methyl(Z,2E)-5-[1-(4-chlorophenyl)pyrazol-3-yl]oxy-2-methoxyimino-4-methyl-pent-3-enoate and E-isomer from the previous reaction have been dissolved in 3.0 ml THF. 2.0 ml 40% aqueous methylamine have been added at ambient temperature with stirring which was continued over night. After removal of the solvent in vacuo the mixture was purified by chromatography on silica with a heptane/ethyl acetate gradient. 90 mg of the desired Z-isomer have been collected. 1H-NMR (CDCl3): δ=2.03 (s); 2.85 (d); 3.97 (s); 4.64 (s); 5.87 (s); 6.02 (d); 6.65 (br); 7.35 (d); 7.50 (d); 7.67 (d).