Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([O:35][C:36](=[O:45])[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH2:26][CH2:27][CH2:28][OH:29])([CH3:25])[CH3:24])=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)[CH3:2].[C:46](Cl)(=[O:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:38]([O:37][C:36]([O:35][C:3]1([CH2:1][CH3:2])[C:8]2[CH:9]=[C:10]3[N:18]([C:19](=[O:20])[C:7]=2[CH2:6][O:5][C:4]1=[O:34])[CH2:17][C:16]1[C:15]([CH2:21][CH2:22][Si:23]([CH3:25])([CH3:24])[CH2:26][CH2:27][CH2:28][O:29][C:46](=[O:53])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:14]2[CH:30]=[CH:31][CH:32]=[CH:33][C:13]2=[N:12][C:11]3=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCOC(=O)c1ccccc1
Temperature: 21 °C
Reaction time: 5 h

Procedure:
A mixture of Compound 53 (200 mg, 0.32 mmol), 4-dimethylaminopyridine (78 mg, 0.64 mmol), and benzoyl chloride (55 μL, 0.48 mmol) in 6.4 mL of dichloromethane was stirred at 21° C. for 5 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford a crude product, which was chromatographed to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/N(CC)CC)[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([CH:24]([OH:26])[CH3:25])[CH:3]=1>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]([OH:26])[CH3:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6]2[C:7]=1[CH:8]=[CH:9][N:11]=[N:10]2
Reactant: C#Cc1c(Cl)cc(C(C)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Solvent: Clc1ccccc1Cl
Product: CC(O)c1cc(Cl)c2ccnnc2c1-c1cccc(F)c1
Yield: 75.8 %

Procedure:
A solution of 1-{4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluorobiphenyl-2-yl}ethanol (2.3 g, 6.1 mmol) in 1,2-dichlorobenzene (59 mL) was heated in the microwave at 200° C. for 15 minutes. The reaction mixture was concentrated to give a black residue. Purification by flash column chromatography using acetonitrile in dichloromethane (0%-30%) gave the desired product (1.4 g, 74% for 2 steps). LCMS for C16H13ClFN2O (M+H)+: m/z=303.1; Found: 302.9.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([C:7]([NH:9][NH:10][C:11](=[O:29])[C@H:12]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=2)[C@@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[CH3:37][C:38]([Si:41](Cl)([CH3:43])[CH3:42])([CH3:40])[CH3:39]>CN(C=O)C>[Si:41]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1)[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:31][CH:30]=1)=[O:29])([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:43])[CH3:42]
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
To a pre-cooled (0° C.) solution of 4-cyano-N′-((2R,3S)-2-(4-cyano-3-(trifluoromethyl)phenylamino)-3-hydroxybutanoyl)benzohydrazide (1.49 g, 3.45 mmol) in DMF (100 mL) was added imidazole (1.88 g, 27.63 mmol) then TBSCl (2.08 g, 13.82 mmol). The reaction was warmed slowly to room temperature, stirred for 18 h, cooled to 0° C. and quenched with H2O (300 mL). The solution was extracted with EtOAc (250 mL). The organic extract was washed with H2O (2×100 mL) and 5% aq. citric acid (3×80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-30% EtOAc in hexanes) to provide the title compound as a colourless solid (1.05 g, 56%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.06 (dm, J=8.4 Hz, 2H), 7.92 (dm, J=8.4 Hz, 2H), 7.72 (d, J=8.6 Hz, 1H), 7.31 (d, J=2.4 Hz, 1H), 7.11 (dd, J=2.3, 8.6 Hz, 1H), 6.48 (d, J=8.6 Hz, 1H), 4.43 (dq, J=4.5, 6.1 Hz, 1H), 4.35 (dd, J=4.5, 8.4 Hz, 1H), 1.37 (d, J=6.3 Hz, 3H), 0.87 (s, 9H), 0.12 (s, 3H), −0.04 (s, 3H).
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].O([CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])S(C(F)(F)F)(=O)=O>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[CH2:33][C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2CC(F)(F)C(F)(F)F)CC1

Procedure:
L41. (2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was alkylated with 2,2,3,3,3-pentafluoropropyl triflate in analogy to experiment L37 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(2,2,3,3,3-pentafluoro-propyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless oil. MS: 486.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:23]([OH:25])=O)=[CH:15][CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][NH:27][CH3:28].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[CH3:26][N:27]([CH3:28])[C:23]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH2:14][CH:15]=1)=[O:25]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC=C(C(=O)O)c3ccccc32)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1=CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Yield: 48.4 %

Procedure:
A solution of the above crude carboxylic acid (300 mg, ca. 0.87 mmol), dimethylamine (2.0M in THF, 0.88 ml, 1.76 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 338 mg, 1.76 mmol), hydroxybenzotriazole hydrate (178 mg, 1.31 mmol) in DMF (10 ml) was stirred at room temperature for 24 h, poured into water, extracted with EtOAc (three times). The extracts were dried (Na2SO4), concentrated and purified by flash chromatography (hexane/EtOAc 1:0 to 0:1) to give tert-butyl 4-(dimethylcarbamoyl)-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B2) (156 mg). LC-MS: m/e=371.1 (M+H), 315.0 (M+H−C(CH3)3). Rt=3.16 min. 1H-NMR (500 MHz, CDCl3): 7.32-7.27 (m, 2H), 7.13 (t, 1H), 6.97 (d, 1H), 6.00 (t, 1 H), 3.91 (br. d, 2H), 3.04 (br. s, 3H), 2.97 (t, 2H), 2.85 (br. s, 3H), 2.44 (br. s, 2H), 1.85 (m, 2H), 1.70 (d, 2H), 1.40 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH3:17])[CH:13]([C:18]([OH:20])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O.CN(C=O)C>C(Cl)Cl>[Cl:24][C:18]([CH:13]1[CH:14]([CH3:17])[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12]1)=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1CCN(C(=O)OCc2ccccc2)CC1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of 1-(benzyloxycarbonyl)-4-methylpiperidine-3-carboxylic acid (1.28 g, 4.62 mmol) in DCM (40 mL) was added oxalyl chloride (0.930 mL, 10.6 mmol) followed by the drop-wise addition of DMF (0.072 mL, 0.92 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to yield crude benzyl 3-(chlorocarbonyl)-4-methylpiperidine-1-carboxylate (1.4 g, 4.7 mmol) which was dissolved in a mixture of Et2O and MeCN (1:1, 16 mL) and added to a solution of trimethylsilyldiazomethane (2 M in Et2O, 9.47 mL, 18.5 mmol) in Et2O and MeCN (1:1, 16 mL) that was cooled to about 0° C. The resulting mixture was stirred at about 0° C. for about 4 h and quenched by a drop-wise addition of 48% aqueous HBr. The organic solvents were removed and the residue was purified by silica gel chromatography eluting with a gradient of 10-40% EtOAc in heptane. The product-containing fractions were concentrated under reduced pressure to give benzyl 3-(2-bromoacetyl)-4-methylpiperidine-1-carboxylate (0.78 g, 47%): LC/MS (Table 2, Method a) Rt=2.50 min; MS m/z: 356 (M+H)+.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][O:35][CH2:36][C:37](O)=[O:38]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:37](=[O:38])[CH2:36][O:35][CH3:34])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COCC(=O)O
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: COCC(=O)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and methoxyacetic acid (9.2 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]([F:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]([F:14])=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(F)c(Cl)c(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)c(F)cc(C(=O)O)c1Cl
Yield: 99.6 %

Procedure:
12.8 g of this ester are boiled for 11/2 hours with 4 g of NaOH in 100 ml of ethanol/water. After cooling, the mixture is acidified with HCl and filtered under suction. 12 g of the title compound are obtained. Melting point 167°-69° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6]CN)=[CH:2]1.[N+:9]([CH3:12])([O-:11])=[O:10]>>[N+:9]([CH:12]=[CH:6][CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)([O-:11])=[O:10]
Reactant: NCCc1ccoc1
Reactant: C[N+](=O)[O-]
Product: O=[N+]([O-])C=CC1CCOC1
Yield: 55 %

Procedure:
Dichloromethane extraction of tetrahydrofuran-3-carboxaldehyde in water (50%, 2 mL) gave pure aldehyde (0.72 g, 7.2 mM) that was reacted with nitromethane in an analogous manner as used for the preparation of 2-Furan-3-yl-ethylamine above, to yield 3-(2-Nitrovinyl)-tetrahydrofuran (0.57 g, 55% yield) after column chromatography (elution with 30% ethyl acetate/Hexanes). The vinyl-nitro compound was reduced with LAH as described for the synthesis of 2-(furan-2-yl-)ethylamine, except that 1 M HCl/Et2O (5 mL) was added to the filtered solvent prior to evaporation to yield 2-(Tetrahydrofuran-3-yl) ethylamine as the HCl salt (30% yield). ESI-MS (m/z) 116 [M+H]+.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:14]([CH3:16])[CH3:15])[C:5]=1[OH:17].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:31]>>[CH:3]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:14]([CH3:16])[CH3:15])[C:5]=1[OH:17])=[O:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1cc(C(C)(C)C)cc(CN)c1O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)c1cc(C(C)(C)C)cc(C=O)c1O

Procedure:
0.4 g (0.0012 mol) of 2-aminomethyl-4-(1,1-dimethylethyl)-6-isopropylphenol hydrochloride is reacted with 0.17 g of hexamethylenetetramine in 2.5 ml of trifluoroacetic acid in analogy to Example 1. Melting point: 128°-130° C.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:57][CH3:58])=[C:32]([CH2:41][NH:42][C:43](=[O:56])[C:44]3[CH:49]=[CH:48][C:47]([CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][OH:55])=[CH:46][CH:45]=3)[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24]>C1COCC1.C(Cl)Cl>[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:57][CH3:58])=[C:32]([CH2:41][NH:42][C:43](=[O:56])[C:44]3[CH:45]=[CH:46][C:47]([CH2:50][CH2:51][CH2:52][CH2:53][CH:54]=[O:55])=[CH:48][CH:49]=3)[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCCO)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(CCCCC=O)cc1
Yield: 99.7 %

Procedure:
Dess Martin Reagent (432 mg, 1.02 mmol) was added to a solution of Intermediate 34 (250 mg, 0.51 mmol) in THF (5 mL) and DCM (5 mL). The resultant mixture was stirred at rt for 2 h. The solvent was removed in vacuo and the crude solid was purified by column chromatography on silica gel eluting with 0-10% DCM-MeOH to afford the title compound as a white solid (250 mg). ES/MS calcd. for C28H38N5O3+ 492.3. found m/z=492.3 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][SH:28]>>[CH3:23][O:24][C:25](=[O:29])[CH2:26][CH2:27][S:28][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:22])=[N:4][CH:3]=1
Reactant: COC(=O)CCS
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Product: COC(=O)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 3-mercaptopropionic acid methyl ester.
Reaction SMILES: [C:1]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2]1.F[B-](F)(F)F.[CH3:18][O+:19]([CH3:21])C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:18][O:19][C:21]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:1][N:2]=1
Reactant: O=C1CCCCCCCCCN1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=NCCCCCCCCCC1
Temperature: 25 °C

Procedure:
2-Azacycloundecanone (0.87 g) was dissolved in 20 mL methylene chloride and stirred at room temperature under nitrogen. 1.5 g Trimethyloxonium tetrafluoroborate was added and the reaction stirred overnight. The mixture was added to saturated aqueous sodium bicarbonate and extracted with methylene chloride (2×). The combined organic layers were washed with brine, dried over magnesium sulfate, and the solvent evaporated to provide crude 2-methoxyazacyclododec-1-ene.
Reaction SMILES: Cl.Cl[CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][SH:23].[H-].[Na+]>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][S:23][CH:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: ClC(CCc1ccccc1)Cn1ccnc1
Reactant: SCc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(CSC(CCc2ccccc2)Cn2ccnc2)cc1Cl

Procedure:
600 Mg. of 1-(2-chloro-4-phenylbutyl) imidazole hydrochloride was added to a fully reacted mixture of 1.1 g. of 3,4-dichlorobenzylmercaptan and 400 mg. of 56% sodium hydride dispersion in mineral oil in 30 ml. of tetrahydrofuran. After stirring under reflux for 12 hours the solvent was evaporated under vacuum and 150 ml. of ether was added. The resulting mixture was washed twice with water and the ethereal solution dried and evaporated to afford 1-[2-(3,4-dichlorobenzylthio)-4-phenylbutyl]imidazole, as an oil. This material was converted to the oxalate salt by treatment of an ethereal solution wih oxalic acid in ether until precipitation was complete, which salt was recrystallized from acetone/ethyl acetate as colorless flakes (660 mg.), m.p. 143.5°-146° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.C1(C2[C:27](C3N=CN(C4C=CC=CC=4)C=3)=[C:26](C(F)(F)F)[O:25]N=2)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:26](=[O:25])[CH3:27])=[C:11]([C:13]([F:14])([F:16])[F:15])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1cn(-c2ccccc2)cn1
Reactant: Fc1ccc(-c2cc(C(F)(F)F)on2)cc1
Product: CC(=O)c1c(-c2ccc(F)cc2)noc1C(F)(F)F
Yield: 85 %

Procedure:
As described for Example 1e, 3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazole (50.0 mg, 216 mmol), instead of 3-phenyl-4-(1-phenyl-1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole, was converted to the title compound (50.2 mg, 85%) which was obtained as a light yellow oil. MS: m/e=272.1 [M−H]−.
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([OH:32])=O>>[CH3:24][C:25]1[N:26]=[C:27]([N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([CH2:39][C:40]3[CH:41]=[CH:42][C:43]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:45]=3)[C:34]2=[O:50])[S:28][C:29]=1[C:30]([NH2:7])=[O:32]
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in Example 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-4-methyl-2-(4-methyl-2-oxo-3-(4-(trifluoromethyl)-benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.73 (d, J=8.2 Hz, 2H), 7.56 (d, J=8.2 Hz, 2H), 7.32 (br, 2H), 4.66 (d, J=16.0 Hz, 1H), 4.45 (d, J=16.0 Hz, 1H), 4.21 (t, J=9.6 Hz, 1H), 3.83-3.76 (m, 1H), 3.57 (dd, J=10.2, 6.8 Hz, 1H), 2.46 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 399.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[N+:36]([O-])=O)[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[C:23]([N+:30]([O-])=O)[CH:22]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:30][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[NH2:27])[O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:7][C:6]1[CH:33]=[CH:34][C:35]([NH2:36])=[C:4]([NH2:1])[CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccccc2Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccccc2-c2ccccc2Oc2ccc(N)c(N)c2)cc1N
Yield: 88 %

Procedure:
A stirred mixture of 2,2'-bis(3,4-dinitrophenoxy)biphenyl (22.0 g, 0.0425 mole) and 10 weight percent palladium on charcoal (2.2 g) in absolute ethanol (500 ml) was heated to reflux under nitrogen, and a solution of hydrazine hydrate (43 ml) in ethanol (100 ml) was added dropwise over a period of 40 minutes. The reaction mixture was heated at reflux for 17 hours, chilled in an ice bath, and suction filtered through Celite filter aid into one liter of stirred, cold, concentrated hydrochloric acid. The resulting precipitate of hydrazine hydrochloride and desired tetraamine hydrochloride was collected, partially dried and dissolved in water (1 liter). Concentrated ammonium hydroxide solution (300 ml) was added and the resulting precipitate collected and vacuum dried to produce 14.9 g (88 percent) of 2,2'-bis(3,4-diaminophenoxy)biphenyl). A portion of the product was recrystallized from ethanol-water to provide an analytical sample (melting point 172°-174°C).
Reaction SMILES: [OH-].[Li+].[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([O:18]CCCC)=[O:17])=[CH:13][CH:14]=2)[C@H:9]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:8][C@@H:7]1[CH3:30])(=[O:5])[CH3:4]>O.C(O)C>[C:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=2)[C@H:9]([NH:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:8][C@@H:7]1[CH3:30])(=[O:5])[CH3:4]
Reactant: CCCCOC(=O)c1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reaction time: 16 h
Yield: 85 %

Procedure:
Lithium hydroxide (0.365 g, 15.23 mmol) in water (5 mL) was added to a solution of butyl (2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinecarboxylate (for a preparation, see Intermediate 65) (1.982 g, 5.08 mmol) in ethanol (5 ml) and the mixture was stirred for 16 h at this temperature then concentrated in vacuo. The aqueous residue was diluted with water (5 mL) and the aqueous phase was washed with Et2O (10 mL). The aqueous layer was acidified with a 2M HCl aqueous solution (pH<2) and extracted with EtOAc (2×10 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo to give (2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinecarboxylic acid (1.45 g, 4.34 mmol, 85% yield) as a colourless crystalline solid
Reaction SMILES: [CH:1]1[C:18]2[CH:17]=[CH:16][C:15]3[C:6](=[CH:7][C:8]([CH2:19][NH:20][C:21]([CH3:26])([CH2:24][OH:25])[CH2:22][OH:23])=[C:9]4[C:14]=3[CH:13]=[CH:12][CH:11]=[CH:10]4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:27](O)(=[O:31])[CH:28]([CH3:30])[OH:29]>>[C:27]([O:25][CH2:24][C:21]([NH:20][CH2:19][C:8]1[CH:7]=[C:6]2[C:15](=[C:14]3[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:16]=[CH:17][C:18]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=1)([CH3:26])[CH2:22][OH:23])(=[O:31])[CH:28]([CH3:30])[OH:29]
Reactant: CC(O)C(=O)O
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Product: CC(O)C(=O)OCC(C)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Yield: 44.1 %

Procedure:
A mixture of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol free base (ID) (3.45 g, 10 mmol) and lactic acid (Fisher Scientific Co., 711 Forbes Ave., Pittsburgh, PA, 15219, 85% liquid, 1.04 g, 10 mmol) in CH3ON (500 mL) was brought to reflux and filtered through a glass fritted funnel. The solvent was removed by rotary evaporation to give a crude white solid. This was crystallized (CH3OH/Et2O) 3× to give 1.84 g (42.2%) of 2-((6-chrysenylmethyl)amino)-2-methyl-1,3-propanediol lactate mp 163°-164°, (C, H, N).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][CH:18]1[O:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][CH2:19]1)(=O)=O>>[O:23]1[C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[O:20][CH2:19][CH:18]1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OCC1COc2ccccc2O1
Reactant: O=Cc1cccc2[nH]ccc12
Product: O=Cc1cccc2c1ccn2CC1COc2ccccc2O1

Procedure:
The same procedures used in Example 1 were repeated except for using 870 mg of indole-4-carbaldehyde and 2-benzodioxanylmethyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 699 mg of 1-(2-benzodioxanylmethyl)indole-4-carbaldehyde as a pale yellow oily substance. The yield thereof was found to be 40%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]>>[CH3:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1ccccc1I
Product: Cc1ccccc1-n1ccc2ccccc21

Procedure:
Prepared by Procedure C and Scheme O using 1H-indole and 1-iodo-2-methylbenzene: ESMS m/e: 208.0 (M+H)+.