Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:3]=1.[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>C(O)(=O)C>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:1][C:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[N:3]=2)=[CH:17][CH:16]=1
Reactant: NC1=NN(c2ccc(Cl)cc2)CC1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Product: Clc1ccc(C=NC2=NN(c3ccc(Cl)cc3)CC2)cc1
Yield: 93 %

Procedure:
3-Amino-1-(4-chlorophenyl)-2-pyrazoline (prepared in Reference Example 6 of our European patent specification No. 22-578) (1.95 g) in S.V.M. (5 ml) was mixed with excess 4-chlorobenzaldehyde (1.50 g) and the mixture was heated to reflux after the addition of 1 drop of glacial acetic acid. A virtually clear solution formed which rapidly crystallised to form a bright orange product which was collected, washed with S.V.M. and dried in vacuo to produce 2.95 g 3-(4-chlorobenzylideneamino)-1-(4-chlorophenyl)-2-pyrazoline, m.p. 193°-195° (decomp).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[CH2:16]([N:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[C:23](=[O:30])[C:22]1=[O:31])[CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1>[OH:30][C:23]1([C:7]2[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=2)[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:29]=2[N:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:22]1=[O:31]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCCCCN1C(=O)C(=O)c2cnccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 152 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (0.27 g, 1.90 mmol) in THF (10.0 mL) was added iso-propylmagnesium chloride (0.97 mL, 2 M solution in THF, 1.90 mmol) slowly at 0° C. The mixture was allowed to stir at ambient temperature for 1 hour followed by the addition of 1-pentyl-1H-pyrrolo[3,2-c]pyridine-2,3-dione (0.21 g, 0.96 mmol). The resulting mixture was stirred at ambient temperature overnight, quenched with saturated ammonium chloride (20.0 mL). The mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, ½) to give the title compound (0.52 g, 40%) as a white solid: mp 193-195° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.30 (d, 1H), 7.88 (s, 1H), 7.22 (s, 1H), 7.04 (d, 1H), 6.64 (s, 1H), 6.21 (s, 1H), 5.93-5.87 (m, 2H), 3.70-3.50 (m, 2H), 1.63-1.48 (m, 2H), 1.36-1.23 (m, 4H), 0.84 (t, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 151.4, 150.6, 148.5, 147.3, 143.4, 140.0, 128.6, 119.6, 107.1, 104.6, 101.2, 97.8, 73.9, 28.9, 26.8, 22.4, 14.4; MS (ES+) m/z 357.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[NH2:13][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:15][C:16]([OH:18])=[O:17]>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:13]([CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:16]([OH:18])=[O:17])[C:6](=[O:8])[C:5]2=[CH:11][CH:12]=1
Reactant: NC(CC(=O)O)c1ccccc1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(=O)N(C(CC(=O)O)c1ccccc1)C2=O
Yield: 54.6 %

Procedure:
A stirred mixture of 4-methylphthalic acid anhydride (1.62 g, 10.0 mmol) and 3-amino-3-phenylpropionic acid (1.65 g, 10.0 mmol) in 15 mL of acetic acid under nitrogen was heated to reflux for 6 hours. The resulting reaction solution was concentrated in vacuo to an oil which was crystallized from 20 mL of a 1/1 mixture of ethyl acetate/hexane to afford 1.69 g (55%) of 3-(4-methylphthalimido)-3-phenylpropionic acid as an off-white powder: 1H NMR (DMSO-d6) δ 12.5 (br s, 1 H, COOH), 7.85-7.55 (m, 3 H, Ar),7.55-7.2 (m, 5H, Ar), 5.68 (dd, 1 H, J=9, 7 Hz, CH), 3.51 (dd, 1 H, J=9, 16.5 Hz), 3.29 (dd, 1 H, J=9, 16.5 Hz), 2.47 (s, 3 H, CH3). Anal. Calcd for C18H15N1O4. Theory; C, 69.89, H, 4.89, N, 4.53. Found: C, 69.45, H, 4.93, N, 4.55. HPLC: 95%.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9]C)=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C.CCOC(C)=O.O>[F:1][C:2]1[C:3]([OH:9])=[N:4][C:5]([F:8])=[CH:6][CH:7]=1
Reactant: COc1nc(F)ccc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1nc(F)ccc1F
Temperature: 82.5 °C
Yield: 55.7 %

Procedure:
To 3,6-difluoro-2-methoxypyridine (21.5 g, 148 mmol) in acetonitrile (250 ml) was added sodium iodide (66.6 g, 445 mmol) and chlorotrimethylsilane (56.8 ml, 445 mmol). The resulting mixture was heated at 80-85° C. for 2.5 hr. The mixture was cooled to ambient temperature and diluted with EtOAc (300 mL) and water (300 mL) and vigorously stirred for another hr. The layers were separated, and the aqueous phase was extracted with additional ethyl acetate (200 mL). The combined organic layers were washed sequentially with 0.6 N aqueous HCl (250 mL) and brine (250 mL) and concentrated in vacuo to yield a slurry. The slurry was filtered and rinsed three times with cold acetonitrile to yield 10.8 g of desired product as a white solid. The filtrate was concentrated and purified by flash chromatography over silica gel (heptanes:ethyl acetate gradient) to give an additional 4.2 g (77% yield combined) of 3,6-difluoro-2-hydroxypyridine as a white solid. LCMS (m/z): 132.0 [M+H]+; retention time=0.47 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11]Br.[O:14]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:13])[CH2:11][N:30]1[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29]1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: Cc1cccc(C)c1NC(=O)CBr
Product: Cc1cccc(C)c1NC(=O)CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (18) synthesized in Reference Example 18 and the compound (4) synthesized in Reference Example 4 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5](O)[CH2:4][C:3]1([CH3:12])[CH3:11].N(OC(C)(C)C)=O.N1C=CC=CC=1.[CH2:26]([O:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1N)[CH:27]=[CH2:28]>ClC1C=CC=CC=1>[O:29]1[C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[CH:27]([CH2:28][O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:26]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: C=CCOc1ccccc1N
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Solvent: Clc1ccccc1
Product: CC1(C)CCCC(C)(C)N1OCC1COc2ccccc21
Yield: 58.9 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine, 3.10 g (30 mmol) of tert-butyl nitrite, 2.4 g (25 mmol) of pyridine, 7.5 mg (0.012 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) mmol) in 100 mL of chlorobenzene and 5.60 g (25 mmol) of 2-allyloxyaniline in 20 mL of chlorobenzene. The crude product obtained is purified by vacuum flash chromatography (25% ethyl acetate/heptane) to give 2.13 g of a viscous liquid in 59.0% yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17]O>>[O:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1
Reactant: OCc1ncco1
Reactant: COC(=O)c1ccc(O)cn1
Product: O=C(O)c1ccc(OCc2ncco2)cn1

Procedure:
The title compound was synthesized analogously according to Method S starting from methyl 5-hydroxypicolinate (Molbridge) and oxazol-2-ylmethanol (AstaTech). MS m/z=237.9 [M+H]+. Calculated for C9H7N3O3S. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.59 (s, 2H) 7.86 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.17 Hz, 1H) 8.83 (d, J=1.37 Hz, 1H) 9.14 (d, J=1.96 Hz, 1H)
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(OC)=O)=CN=3)CC3CC(CC(C3)C1)C2.[CH:26]1([C:29]2[C:30]([O:40][CH2:41][C:42]34[CH2:52][C:46]5([F:53])[CH2:47][C:48]([F:51])([CH2:50][C:44]([F:54])([CH2:45]5)[CH2:43]3)[CH2:49]4)=[CH:31][C:32]([F:39])=[C:33]([CH:38]=2)[C:34]([O:36]C)=[O:35])[CH2:28][CH2:27]1>>[CH:26]1([C:29]2[C:30]([O:40][CH2:41][C:42]34[CH2:52][C:46]5([F:53])[CH2:47][C:48]([F:51])([CH2:50][C:44]([F:54])([CH2:45]5)[CH2:43]3)[CH2:49]4)=[CH:31][C:32]([F:39])=[C:33]([CH:38]=2)[C:34]([OH:36])=[O:35])[CH2:27][CH2:28]1
Reactant: COC(=O)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F
Agent: COC(=O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(O)c1cc(C2CC2)c(OCC23CC4(F)CC(F)(CC(F)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 150 step 4 and making variations as required to replace methyl 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinate with methyl 5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoate, the title compound was obtained as a colorless solid (0.48 g, quant.): MS (ES−) m/z 397.2 (M−1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[C:13]2[N:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1)[CH3:2].S(=O)(=O)(O)O.[N+:29]([O-])([OH:31])=[O:30]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:29]([O-:31])=[O:30])=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[O:23])[C:13]2[N:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1)[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCCc1ccnc2c(=O)[nH]c(-c3ccccc3OCC)nc12
Agent: O=S(=O)(O)O
Product: CCCc1ccnc2c(=O)[nH]c(-c3cc([N+](=O)[O-])ccc3OCC)nc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 77 %

Procedure:
A solution of 2-(2-ethoxyphenyl)-8-n-propylpyrido-[3,2-d]pyrimidin-4(3H)-one (Preparation 8; 0.80 g, 0.0026 mol) in a mixture of concentrated sulphuric acid (5.4 ml) and concentrated nitric acid (0.20 ml) was stirred at ambient temperature for 4.5 hours. The mixture was then poured cautiously into stirred ice/water (50 g) and the resulting mixture extracted with a methanol:dichloromethane mixture (1:9, 3×50 ml). The organic extracts were combined, dried (MgSO4) and evaporated under vacuum, and the residue crystallised from ethyl acetate:methanol to give the title compound as an off-white solid (0.71 g, 77%), m.p.257°-259° C. Found: C,61.28; H,5.11; N,15.60. C18H18N4O4 requires C,61.01; H,5.12; N,15.81%.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[Cl:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1.C(N(CC)CC)C>C(O)C>[ClH:18].[CH3:27][C:23]1[N:22]=[C:21]([CH2:20][CH2:19][N:12]2[CH2:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=3)[CH2:14][CH2:13]2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(CCCl)n1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cccc(CCN2CC=C(c3cccc(C(F)(F)F)c3)CC2)n1
Yield: 36.4 %

Procedure:
By operating as described in Example 1, 5.7 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine are reacted with 5.2 g of 2-(2-chloroethyl)-6-methylpyridine hydrochloride in the presence of 7.5 ml of triethylamine in 60 ml of ethanol at reflux for 18 hours to obtain 3.5 g of 1-[2-(6-methyl-2-pyridyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride; m.p. 207°-210° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:9]2[N:10]=[CH:11][N:12]=[C:8]2[N:7]=[CH:6][CH:5]=1)[CH3:3].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:13][C:2]([C:4]1[N:9]2[N:10]=[CH:11][N:12]=[C:8]2[N:7]=[CH:6][CH:5]=1)([CH3:1])[CH3:3]
Reactant: CC(C)c1ccnc2ncnn12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccnc2ncnn12

Procedure:
A mixture of 7-(1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine (4.18 g), N-bromosuccinimide (4.59 g), and dibenzoylperoxide (70 mg) in tetrachloromethane (105 ml) was stirred and heated under reflux for 11 hours. The mixture was filtered and the solvent was removed from the filtrate to give 7-(1-bromo-1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 2.94 g.
Reaction SMILES: C(N1C(=O)C2=CC=CC=C2C1=O)C1C=CC=CC=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(=O)NC(=O)C2=CC=CC=C12.[K].[CH3:39][C:40]1([CH3:51])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]([CH3:50])([CH3:49])[NH:41]1>CI.[Mg].C1(C)C=CC=CC=1.C(OCC)C>[CH2:19]([N:41]1[C:40]([CH3:51])([CH3:39])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]1([CH3:50])[CH3:49])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)NC(C)(C)c2ccccc21
Reactant: BrCc1ccccc1
Agent: O=C1NC(=O)c2ccccc21
Agent: O=C1c2ccccc2C(=O)N1Cc1ccccc1
Agent: [K]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CI
Product: CC1(C)c2ccccc2C(C)(C)N1Cc1ccccc1
Yield: 37 %

Procedure:
The synthesis set up by Rizzardo and coworkers is of the greatest practical interest, and comprises the synthesis of N-benzylpthalimide from benzyl bromide and potassium phthalimide, followed by its alkylation with a Grignard reagent. In the synthesis of 1,1,3,3-tetramethylisoindoline, for example, the Grignard reagent was prepared starting from methyl iodide and magnesium using, as solvents, ethyl ether and toluene (in succession): after 4 hours at reflux, N-benzyl-1,1,3,3-tetramethylisoindoline is obtained (37% yield), which is then treated with hydrogen (4 atmospheres; room temperature) in glacial acetic acid and in the presence of palladium-based catalysts (5% on coal). After 3 hours of reaction, 1,1,3,3-tetramethylisoindoline is obtained (II, R═CH3) with a yield of 96% (P. G. Griffiths, G. Moad, E. Rizzardo, D. H. Solomon, “Australian Journal of Chemistry” 1983, 36, 397).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])[CH:2]=[CH2:3].ClC1C=C(C(OO)=[O:19])C=CC=1.S(=O)(O)[O-].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[O:19]1[CH2:3][CH:2]1[CH2:1][N:4]1[CH2:8][C:7](=[O:9])[NH:6][C:5]1=[O:10]
Reactant: C=CCN1CC(=O)NC1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CN(CC2CO2)C(=O)N1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
A reaction solution of 1-(2-propenyl)-2,4-imidazolidinedione (0.036 mol) and 3-chloro-benzenecarboperoxoic acid (0.043 mol, 70.75%) in DCM (25 ml) was stirred for 2 hours at room temperature. An aqueous solution of bisulfite was added and the mixture was stirred for 10 minutes. Na2CO3 was added and this mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent evaporated, yielding 5 g of (±)-1-(oxiranylmethyl)-2,4-imidazolidinedione (intermediate 18).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:21])[CH2:8][O:9][C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH2:20])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:4])[CH3:3].[Cl:22][C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:2]([O:6][C:7](=[O:21])[CH2:8][O:9][C:10]1[C:19]2[CH2:18][CH2:17][CH2:16][C@@H:15]([NH:20][S:30]([C:25]3[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=3)(=[O:32])=[O:31])[C:14]=2[CH:13]=[CH:12][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2NS(=O)(=O)c1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
A solution of dimethyl-pyridin-4-yl-amine (1.17 g, 9.60 mmol) in tetrahydrofuran (10 mL) was added dropwise to a solution of (R)-(5-amino-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester hydrochloride salt (1 g, 3.18 mmol) and 3-chloro-4-fluoro-benzenesulfonyl chloride (0.68 mL, 4.77 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature overnight, and then concentrated. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford (R)-[5-(3-chloro-4-fluoro-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (1.4 g, 93.8%) as a white solid. MS calcd. for C22H25ClFNO5S 469, obsd 470 (ESI+) [(M+H)+].
Reaction SMILES: [C:1]([N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.[Br:38]Br>O1CCCC1>[C:1]([N:20]1[C:24]([Br:38])=[N:23][CH:22]=[N:21]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2cncn2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ncnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -70 °C
Yield: 40.3 %

Procedure:
A stirred solution of 1-trityl-1,2,4-triazole (15.55 g, prepared as described in Example 1) and N,N,N',N'-tetramethylethylenediamine (5.8 g) in dry tetrahydrofuran (500 ml) was cooled to -70° C. under nitrogen and treated dropwise with n-butyllithium (37.5 ml, 1.6M in hexane). The deep-red solution was stirred at -70° C. for twenty minutes, then treated dropwise with a solution of bromine (10.4 g) in dry tetrahydrofuran (10 ml). The now brownish-yellow solution was allowed to warm to -20° C., quenched with 0.1M sodium thiosulphate solution (150 ml), and extracted with dichloromethane (500 ml). The organic layer was washed with water (4×100 ml), dried and evaporated. The residue was chromatographed on silica, using dichloromethane-ether (25:2) as eluant, to give 1-trityl-5-bromo-1,2,4-triazole (7.86 g, m.p. 239-241° C.). NMR (CDCl3): δ 7.1-7.3(15H,m), 7.95(1H,s).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12][CH2:11]2.N1C=CC=CC=1>O>[N:10]12[CH2:17][CH2:16][CH2:15][C:14]1([CH2:18][CH2:19][NH:20][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:13][CH2:12][CH2:11]2
Reactant: NCCC12CCCN1CCC2
Reactant: N#Cc1ccccc1F
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccccc1NCCC12CCCN1CCC2
Yield: 95.8 %

Procedure:
2-Fluorobenzonitrile (1.00 g, 8.26 mmol) and 2-(1-azabicyclo[3.3.0]octan-5-yl)ethylamine (3.15 g, 20.4 mmol) were added into anhydrous pyridine (10.0 ml) to react the mixture in a sealed tube for 10.5 hours at 180° C. After addition of water subsequent to concentration in vacuo, the reaction mixture was extracted by ethyl acetate, dried over anhydrous sodium sulfate, concentrated in vacuo, and refined by column chromatography to afford the desired compound (2.02 g, 95.8%), as a colorless liquid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[C:16](\[CH3:22])/[C:17](OCC)=[O:18])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[CH2:10][CH2:11][C@H:12](/[CH:15]=[C:16](\[CH3:22])/[CH2:17][OH:18])[CH2:13][CH2:14]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C(C)=C/[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C(=C\[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1)CO
Reaction time: 0.5 h

Procedure:
To a solution of 300 mg (0.95 mmol) of enoate (19) in 2.0 mL of anhydrous tetrahydrofuran at 25° C. was added 18 mg (0.43 mmol) of lithium aluminum hydride and the resulting mixture was allowed to stir for 30 min. The reaction was quenched by the slow addition of saturated Rochelle's salt and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with two portions of ethyl acetate. The combined organic extracts were washed with water and brine and then drive over MgSO4. Evaporation and flash chromatography (elution with 1:10 ethyl acetate-hexane) gave 220 mg of the allyic alcohol (20). 1H NMR (300 MHz, CDCl3) δ 5.34 (d), 3.96 (d), 3.85 (m), 2.26-2.18 (m), 1.64 (d), 1.61-1.34 (m), 1.82 (s), 0.0 (s).
Reaction SMILES: [OH-].[Na+].C1COCC1.[C:8]1([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:10][CH:9]=1>CO>[C:8]1([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:9]=[CH:10][C:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[N:26][CH:27]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccccc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccccc3)cc2)cn1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.1 mL, 0.30 mmol) was added to a THF (1 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(2-(([1,1′-biphenyl]-4-ylamino)methyl)phenyl)picolinamido)propanoate (73 mg, 0.15 mmol) and the homogeneous mixture was stirred at room temperature. After 3 h the resulting mixture was concentrated in vacuo, suspended in water, and acidified with 2M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:15]=[N:16][NH:17][C:18]=1[C:19]([O:21]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl.[CH3:27][C@H:28]1[C@H:36]([NH2:37])[CH2:35][C@H:31]2[C:32]([CH3:34])([CH3:33])[C@@H:29]1[CH2:30]2.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.[Cl-].[Na+].O.CN(C=O)C.CCOC(C)=O.C1COCC1.CO>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[N:15]=[N:16][NH:17][C:18]=1[C:19]([NH:37][C@@H:36]1[CH2:35][C@H:31]2[CH2:30][C@@H:29]([C:32]2([CH3:34])[CH3:33])[C@H:28]1[CH3:27])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1[C@H](N)C[C@@H]2C[C@H]1C2(C)C
Reactant: CCOC(=O)c1[nH]nnc1-c1ccccc1Oc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1[C@H]2C[C@H](C[C@H]1NC(=O)c1[nH]nnc1-c1ccccc1Oc1ccccc1)C2(C)C
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of ester (9) (1.0 equiv) in 2.5:1 THF/MeOH (0.5 M) was treated with a solution of lithium hydroxide (3.0 equiv) in water (1.6 M), and the resulting mixture was stirred at 50° C. overnight, cooled to room temperature, acidified with 1M HCl, diluted with brine and extracted with AcOEt (3×). The combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The pale yellow foam obtained was dissolved in dry DMF (0.4 M) and treated with (−)-isopinocampheyl amine (12) (1.0 equiv), followed by triethylamine (1.0 equiv) and HBTU (1.0 equiv). The resulting solution was stirred at rt for 1 h, diluted with brine and AcOEt. The layers were separated and the aqueous one was washed with brine (2×), 1M HCl and brine (2×), dried (MgSO4), filtered and concentrated under reduced pressure to provide 4-(2-phenoxyphenyl)-N-((1R,2R,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)-1H-1,2,3-triazole-5-carboxamide (13) as a pale yellow foam and was used without further purification.