Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N+:32]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33].[C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51]O)=[CH:46][CH:45]=1)#[N:43]>C1COCC1.O>[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:51][CH2:50][C:47]2[CH:48]=[CH:49][C:44]([C:42]#[N:43])=[CH:45][CH:46]=2)[CH:36]=1)([O-:34])=[O:33]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCOc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.9 %

Procedure:
Triphenylphosphine (11.3 g; 43.1 mmol) and diethylazodicarboxylate (7.5 g; 43 mmol) were dissolved in THF (250 mL) under nitrogen at 0° C. After 5 minutes, 3-nitrophenol (5.00 g; 35.9 mmol) and 2-(4-cyanophenyl)ethanol (6.3 g; 43 mmol) were added. The cooling bath was removed and the mixture stirred for 2 days at room temperature. A new batch was prepared as above and the two were combined before work-up. Water was added and the THF was evaporated. The mixture was extracted with EtOAc, and the organic phase was washed with aqueous 0.2M NaOH and brine, dried (Na2SO4) and the solvent removed in vacuo. Purification by flash chromatography (SiO2; toluene) and recrystallization from CH2Cl2:EtOH afforded 3.07 g (32%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[O:41][C:42]([CH3:45])=[N:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[O:41][C:42]([CH3:45])=[N:43][N:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnc(C)o4)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnc(C)o4)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.36 g) in methylene chloride (10.8 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.12 g) in methylene chloride (7.2 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 238) (230 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][C:13](O)=[O:14].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:12][C:13]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:14]
Reactant: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Reactant: Nc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(CC(c1ccccc1)N1Cc2ccccc2C1=O)Nc1ccccn1

Procedure:
3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid (0.42 mmol, 1 eq), 2-amino pyridine (1.5 eq), HBTU [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphat], (1.5 eq) and N-ethyl diisopropylamine (1.5 eq) are suspended in chloroform and reacted in the microwave (90 min, 120° C., Emrys Optimizer). The resulting mixture is partitioned between chloroform and water. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. The crude product is dissolved in DMSO and purified by prep. LC/MS (reversed phase). 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide (“A1”) is obtained as brown solid (36% yield); ES-MS (MH+)=358.2; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 10.72 (s, 1H), 8.29 (d, 1H, 4.8 Hz), 7.97 (d, 1H, 8.3 Hz), 7.73-7.27 (m, 10H), 7.08-7.05 (m, 1H), 5.95-5.92 (m, 1H), 4.62 (d, 1H, 17.5 Hz), 4.18 (d, 1H, 17.5 Hz), 3.39-3.32 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](Cl)=[O:24])=[CH:19][CH:18]=1>CCOCC>[C:1]1([NH:7][NH:8][C:23](=[O:24])[C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NNc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NNc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60111.8 %

Procedure:
A mixture of phenylhydrazine (25 ml, 0.25 mmole) and triethylamine (35 ml, 0.25 mmole) in anhydrous ether (500 ml) was cooled down to -5° to -10° C. (ice-salt bath) under nitrogen and treated dropwise, over a 30 minute period, with 4-fluorobenzene carbonyl chloride (30 ml, 0.25 mole). The reaction mixture was warmed to room temperature, stirred for 3.0 hours, then filtered, washing the solids well with ether (200 ml). The solids were dissolved in dichloromethane (600 ml), stripped to near dryness, suspended in hexane (600 ml) and filtered. The clear filtrate was evaporated to dryness, triturated with tetrahydrofuran (700 ml) and filtered, washing the solids well with tetrahydrofuran (100 ml). The filtrate was evaporated to dryness and dried in vacuo to give a crude product (34.6 g) contaminated with two other components.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([NH:42][C:43](=[O:51])[CH2:44][N:45]1[CH2:46][CH2:47][N:48]([C:32]([N:12]2[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:49][CH2:50]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)NC(=O)CN1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with N-tert-butyl-2-piperazin-1-yl-acetamide (Enamine-BB) to give the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25]C)[C:15]2[C:20]([CH:21]=[C:22](C)[CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([OH:46])=O>[OH-].[OH-].[Pd+2]>[NH:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:25])[C:15]2[C:20]([CH2:21][CH2:22][CH3:23])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:46]
Reactant: CCN(c1ncccc1C=C(C)C)C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc[nH]1
Agent: [Pd+2]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [OH-]
Product: CCCc1cccnc1N(C)C1CCN(C(=O)c2ccc[nH]2)CC1

Procedure:
Following the general procedure of EXAMPLE 20 and making non-critical variations but starting with 1-benzyl-4-(N-methyl-N-(3-(1-propenyl)-2-pyridinyl)amino)piperidine (XXII, EXAMPLE 14, 0.46 g, mmol), Pearlman's catalyst (0.1 g), CDI (0.46 g, 2.85 mmol) and pyrrole-2-carboxylic acid (0.32 g, 2.85 mmol), the title compound is obtained, mp 88°-90°.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:11]([C:24](O)=[O:25])=[N:12][CH:13]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH2:62]>CN(C=O)C>[CH3:58][O:59][C:60](=[O:63])[CH2:61][NH:62][C:24]([C:11]1[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:15][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][N:12]=1)=[O:25]
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid HCl, 2, (8.06 g, 21.7 mmol) in DMF (100 mL) at 0° C. under N2 is added diisopropylethylamine (11.35 mL, 65.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (6.23 g, 32.6 mmol) and 1-hydroxybenzotriazole (HOBt) (0.294 g, 2.2 mmol). The solution is stirred for 5 minutes and glycine methyl ester hydrochloride (4.09 g, 32.6 mmol) is added. The reaction is allowed to warm slowly to room temperature and stirred 3 days. The reaction volume is partially concentrated under reduced pressure then diluted with EtOAc and washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered and concentrated under reduced pressure to afford a yellow oil that is purified over silica (EtOAc:heptane gradient 1:1 to 1:0) to afford 3.5 g (40% yield) of the desired product as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.12 (1H, t, J=4.9 Hz), 7.95 (1H, d, J=1.8 Hz), 7.38-7.44 (2H, m), 7.22-7.35 (8H, m), 6.85 (1H, d, J=2.6 Hz), 5.14 (2H, s), 5.03 (2H, s), 4.18 (2H, d, J=5.5 Hz), 3.69 (3H, s). HPLC-MS: m/z 407 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:11]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[F:8].[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([C:10]2[N:11]([C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[N:12]=[C:13]3[C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C=NC1CCCCC1
Reactant: Fc1ccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NC1CCCCC1)N(c1ccc(F)c(Cl)c1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-4-fluoro-phenyl)-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 d under reflux conditions to give the title compound as yellow oil. MS: m/e=496.9 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:33][CH2:34][C:35]([NH:37]O)=[NH:36].C1C2C(C3ON=C(N)N=3)CN(C2)C1>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([C:4]2[O:6][N:37]=[C:35]([CH2:34][Cl:33])[N:36]=2)[CH:7]=1
Reactant: O=C(O)c1cc(Cl)ccc1F
Reactant: N=C(CCl)NO
Agent: CCN=C=NCCCN(C)C
Agent: Nc1noc(C2CN3CCC2C3)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Fc1ccc(Cl)cc1-c1nc(CCl)no1
Yield: 56.3 %

Procedure:
The acyclic intermediate was prepared from 2-fluoro-5-chlorobenzoic acid (550 mg, 3.15 mmol), EDCI (665 mg, 3.47 mmol), HOBT (469 mg, 3.47 mmol) and 2-chloro-N-hydroxy-acetamidine (377 mg, 3.47 mmol) in DMF (10 mL). To effect cyclization to oxadiazole, DMF (15 mL) was added to the intermediate residue and the mixture was heated for 1 hour. The product was purified by flash column chromatography using 10% ethyl acetate in hexane afforded the title compound (438 mg, 56% yield over 2 steps, white solid). 1H NMR (CDCl3) δ (ppm): 8.16 (m, 1H), 7.58 (m, 1H), 7.29 (m, 1H), 4.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:13])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[C:7]([C:8]([Cl:13])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Fluoropyridine-3-carboxylic acid (5.02 g, 35.6 mmol) was suspended in dichloromethane (100 mL), treated with thionyl chloride (13.0 mL, 178 mmol, 5 equiv) and N,N-dimethylformamide (0.138 mL, 1.78 mmol, 0.05 equiv) and placed into a preheated oil bath at 45° C. for 2 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and the residue was concentrated from toluene (2×50 mL), providing the titled compound.
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[CH:6]([NH:8][CH:9]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11])=[S:7].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.C(Cl)Cl>[Cl:17][C:14]([Cl:15])([Cl:16])[CH2:13][O:12][C:10]([CH:9]([P:18]([O:20][CH2:21][CH3:22])([O:23][CH2:24][CH3:25])=[O:19])[N:8]=[CH:6][S:7][CH2:2][C:3](=[O:5])[CH3:4])=[O:11]
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(N=CSCC(C)=O)C(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of chloro-2-propanone (0.470 q., 5.08 mMol) in acetone (4 ml.) is added dropwise during 15 minutes to a rapidly stirring mixture of trichloroethyl α-thioformamido-diethylphosphonoacetate (1.783 g., 4.62 mMol), K2CO3 (0.702 g., 5.08 mMol), and acetone (6 ml.). After having been stirred for 15 hours at room temperature, the mixture is diluted with methylene chloride (30 ml.) and filtered to remove salts. The filtrate is evaporated under reduced pressure to yield 2-oxo-propyl N-(trichloroethoxycarbonyl-diethylphosphonomethyl)-thioformimidate.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].CS(O[CH2:11][C:12]([CH3:25])([CH3:24])[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[C:18]([Br:22])=[C:17]([CH3:23])[CH:16]=1)(=O)=O>CN1CCCC1=O.C(OCC)C>[Br:22][C:18]1[C:17]([CH3:23])=[CH:16][C:15]([O:14][CH2:13][C:12]([CH3:25])([CH3:24])[CH2:11][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][C:19]=1[CH3:21]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(OCC(C)(C)COS(C)(=O)=O)cc(C)c1Br
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: Cc1cc(OCC(C)(C)CS(C)(=O)=O)cc(C)c1Br
Temperature: 180 °C

Procedure:
In a microwave vial sodium methanesulfinate (720 mg) is added to a solution of 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropyl methanesulfonate (271 mg) in N-methyl-2-pyrrolidinon (NMP) (8 mL). The mixture is heated to 180° C. for 30 minutes. Then the mixture is diluted with diethylether, washed with water and brine and dried (MgSO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase to give the title compound. Yield: 32 mg; LC (method 8): tR=0.47 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:14]=2)[C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl.CNCCCN=C=NCC.ON1C2C=CC=CC=2N=N1.O[N:37]=[C:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=1>CN(C)C=O>[N:1]1([C:6]2[CH:14]=[C:10]([C:11]3[O:13][N:45]=[C:38]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)[N:37]=3)[CH:9]=[N:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cncc(-n2cccc2)c1
Agent: CCN=C=NCCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: c1cncc(-c2noc(-c3cncc(-n4cccc4)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-(1H-pyrrol-1-yl)nicotinic acid (Maybridge, 188 mg, 1.00 mmol) in dimethylformamide (anhydrous, 5 mL) was added N-(3-methylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (Aldrich, 192 mg, 1.00 mmol) and 1-hydroxybenzotriazole (HOBT) hydrate (Fluka, 153 mg, 1.00 mmol). The mixture was stirred at ambient temperature for 20 minutes. N′-Hydroxynicotinimidamide (137 mg, 1.0 mmol) was added and the mixture was stirred for 6-10 hours, and then warmed to 140° C. for 2-4 hours. The reaction was cooled to ambient temperature and triturated with water (10 mL). The precipitate was filtered and dried under vacuum to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 6.34-6.44 (m, 2H), 7.60-7.82 (m, 3H), 8.50 (dt, J=8.1, 1.9 Hz, 1H), 8.71 (dd, J=2.5, 1.9 Hz, 1H), 8.84 (dd, J=4.6, 1.5 Hz, 1H), 9.21 (d, J=1.7 Hz, 1H), 9.26 (d, J=2.4 Hz, 1H), 9.31 (d, J=1.7 Hz, 1H) ppm; MS (DCl/NH3) m/z 290 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C(=O)([O-])[O-].[K+].[K+].O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:15]([N:1]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCOCCO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OCCOCCN(Cc1ccccc1)Cc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 50 g (475.56 mmol) of 2-(2-aminoethoxy)ethanol and 144.6 g (1.046 mol) of potassium carbonate in 600 ml of EtOH/60 ml of water is heated to 60° C. To this mixture is added dropwise within one hour 178.95 g (1.046 mol) of benzyl bromide and then the mixture is refluxed for 2 hours, evaporated under vacuum, the residue taken up with 1 liter of methylene chloride, and filtered off from the salts. The filtrate is concentrated under vacuum and purified by flash chromatography (silica gel/mobile phase: methylene chloride/hexane/acetone: 10/5/1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[C:3]=1[C:9]#[N:10].O=P(Cl)(Cl)[Cl:13]>>[Cl:13][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccc[n+]([O-])c1C#N
Product: Cc1ccc(Cl)nc1C#N
Temperature: 25 °C

Procedure:
3-Methylpyridine-2-carbonitrile 1-oxide (8.42 g, 62.8 mmol) was stirred in refluxing POCl3 (60 mL, 646 mmol) for 6 hours. The mixture was cooled to room temperature and slowly poured into ice-water. The resulting beige precipitate was collected by filtration to give the title compound.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])=[CH:3]\[CH2:4][C:5]([OH:7])=[O:6].[CH3:19][O:20][C:21](=[O:30])[C@@H:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)O.CO.C1CCC(N=C=NC2CCCCC2)CC1>CC(OC)(C)C.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21]([C@H:22]([O:6][C:5](=[O:7])[CH2:4][CH:3]=[C:2]([CH3:1])[CH2:8][CH2:9][C:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=1[CH3:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:30]
Reactant: CC1=C(CC/C(C)=C/CC(=O)O)C(C)(C)CCC1
Reactant: COC(=O)[C@H](O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: COC(C)(C)C
Product: COC(=O)[C@H](OC(=O)CC=C(C)CCC1=C(C)CCCC1(C)C)c1ccccc1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a solution of 10.0 g (40 mmol) (E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid [H. S. Corey, J. R. D. Cormick, W. E. Swensen, J. Am. Chem. Soc. 1964, 86, 1884] in 100 ml MTBE were added at r.t. 6.64 g (40 mmol) (R)-(−)-mandelic acid methyl ester [α]D=−144.9 (c=1.04, MeOH) and 1.0 g DMAP. Then a solution of 8.24 g (40 mmol) DCC in 100 ml MTBE was added and the reaction mixture stirred for 3 h, filtered and the residue washed with MTBE. The combined organic phases were concentrated in vacuo and the residue (17.6 g) was purified by flash chromatography (250 g silicagel, hexane/MTBE 9:1) affording 12.2 g (88%) 4-methyl-6-(2,6,6-trimethyl-cyclohex-1-enyl)-hex-3-enoic acid (R)-methoxycarbonyl-phenyl-methyl ester (12) in form of a colorless oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH:2]1[C:6]([OH:8])=[O:7].Cl[Si](C)(C)[CH3:11]>CO>[CH3:11][O:7][C:6]([CH:2]1[NH:3][CH2:4][CH2:5][S:1]1)=[O:8]
Reactant: O=C(O)C1NCCS1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)C1NCCS1
Yield: 125 %

Procedure:
A mixture of (±)-thiazolidine-2-carboxylic acid (1.58 g, 11.9 mmol) and chlorotrimethylsilane (5.1 g, 47 mmol) in methanol (22 mL) was heated at reflux for 5 hours, cooled, and concentrated giving a solid (2.19 g, 100%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(=O)[C:31]([Cl:33])=[O:32].O>C(Cl)Cl>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:31]([Cl:33])=[O:32])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3)CC2)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCc1ccc(CC[C@H]2CC[C@H](CCc3ccccc3C(=O)Cl)CC2)cc1
Temperature: 0 °C

Procedure:
Solution prepared by dissolving 47.2 g of (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzene in 500 ml of methylene chloride was cooled down to 0° C., and 34.7 g of aluminum chloride was added thereto and stirred. Oxalyl chloride in an amount of 33 g was added dropwise little by little thereto, it was raised up to room temperature, and stirred for 2 hours. After finishing of the reaction, it was added to 500 ml of water and extracted with 500 ml of methylene chloride. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 33.2 g of (2-(trans-4-(2-(4-n-propylphenyl)ethyl)cyclohexyl)ethyl)benzoyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:13][CH:14]([C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][N:22]=[CH:23]2)[C:15](O)=[O:16].C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:15](=[O:16])[CH:14]([OH:13])[C:18]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[CH:23]3)=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)C(O)c1cccc2cnccc12
Reactant: CC(C)(C)c1ccc(CN)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Solvent: CO
Product: CC(C)(C)c1ccc(CNC(=O)C(O)c2cccc3cnccc23)cc1

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(tert-butyl)benzylamine and hydroxy(5-isoquinolinyl)acetic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. [α]22D −47.2 (c 0.7, MeOH); MS (ESI+) m/z 349 (M+H)+; MS (ESI−) m/z 347 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.26 (s, 9H), 3.69 (s, 1H), 4.27 (d, J 6.1, 2H), 5.62 (s, 1H), 6.52 (br s, 1H), 7.17 (d, J 8.1, 2H), 7.29 (m, 3H), 7.67 (t, J 8.1, 1H), 7.82 (d, J 7.1, 1H), 8.10 (m, 2H), 8.44 (d, J 5.8, 1H), 8.71 (t, J 6.1, 1H), 9.30 (s, 1H); Anal. Calcd for C22H24N2O2+0.25H2O: C, 74.87; H, 7.00; N, 7.94. Found: C, 75.22; H, 7.40; N, 7.80.