Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[O:14][CH:13]2[N:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18]CC1C=CC([N+]([O-])=O)=CC=1)=[O:17])([CH3:7])[CH3:6])=[N+]=[N-].[H][H]>C(OCC)(=O)C.[Pd].O>[NH2:1][CH2:4][C:5]([C:8]1[O:14][CH:13]2[N:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([OH:18])=[O:17])([CH3:7])[CH3:6]
Reactant: CC(C)(CN=[N+]=[N-])C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)CC2O1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CN)C1=C(C(=O)O)N2C(=O)CC2O1

Procedure:
A solution of 21 mg (0.054 mmol) of p-nitrobenzyl 3-(2-azido-1,1-dimethylethyl)-7-oxo-4-oxa-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 1 ml of ethyl acetate is added via a syringe through a septum stopper to a prehydrogenated mixture, at 0° C., of 60 mg of palladium on charcoal (10%) in 1 ml of ethyl acetate and 0.7 ml of water. After a reaction time of 20 minutes, 5.7 ml of hydrogen have been taken up (theoretical amount 4.9 ml). The reaction mixture is filtered at 0° C., and the aqueous phase is washed twice with 2 ml of pre-cooled ethyl acetate. The aqueous phase contains 8.96 mg of the title compound. UV spectrum in H2O: λmax =271 nm (ε=5000)
Reaction SMILES: [NH3:1].[S:2](=[O:5])([OH:4])[OH:3].[S:6]([O-:9])([O-:8])=[O:7].[NH4+].[NH4+]>>[NH4+:1].[NH4+:1].[NH4+:1].[N:1]([S:2]([O-:5])(=[O:4])=[O:3])([S:6]([O-:9])(=[O:8])=[O:7])[S:2]([O-:4])(=[O:3])=[O:5]
Reactant: N
Reactant: O=S(O)O
Reactant: O=S([O-])[O-]
Agent: [NH4+]
Product: O=S(=O)([O-])N(S(=O)(=O)[O-])S(=O)(=O)[O-]

Procedure:
Diammonium imidobissulfate (NH4SO3)2NH may be prepared by introducing ammonia gas and then sulfurous acid gas into an aqueous solution containing ammonium sulfite to obtain triammonium nitridotrisulfate and heating the obtained nitridotrisulfate in ammonia gas at about 250° C under atmospheric pressure to ammonolyze and then followed by heating at about 300° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]#[N:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=[O:24])=CC=1.[C:28]1([CH3:34])C=CC=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]#[N:16])[CH2:9][CH2:10][C:11]3([O:24][CH2:28][CH2:34][O:14]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Product: N#CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
15 g of 1-(4-Fluoro-phenyl)-4-oxo-cyclohexanecarbonitrile (12) were dissolved in 500 mL of toluene, then 900 mg of p-toluene sulfonic acid were added and the reaction mixture was heated in a Dean-Stark apparatus for 6 h. The mixture was allowed to cool to room temperature and washed twice with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to dryness to yield 17.9 g of the desired product. Rt=1.47 min (Method 5). Detected mass: 262.2 (M+H+).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:10].COCCO.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[CH2:9]([N:11]1[C:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:3]2[C:2]1=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:10]
Reactant: O=C1CCCCC1Cl
Reactant: CCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Solvent: O
Solvent: c1ccncc1
Product: CCn1c2c(c3ccccc31)CCCC2
Temperature: 100 °C
Reaction time: 2 h
Yield: 24.2 %

Procedure:
132.5 g of 2-chloro-cyclohexanone was added to 123.42 g of N-ethyl aniline, 500 ml of methyl cellosolve, 127 g of dry sodium carbonate and 7.9 g of pyridine at 30-40° C. over a period of 1 hour. Reaction mass was heated to 100° C. and stirred for 2 hours. Reaction temperature was further raised to 130° C. and held at this temperature till no more water get distilled. Reaction mass was then worked up to get 48.2 g of crude 9-ethyl-tetrahydrocarbazole of 96.3% GC purity.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:20]([CH2:23]Br)=[N:21][S:22][C:10]=2[C:9]=1[O:25]C(=O)C(C)(C)C)=[O:7])[CH2:2][CH2:3][CH3:4].[NH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33]1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]2[C:20]([CH2:23][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33]3)=[N:21][S:22][C:10]=2[C:9]=1[OH:25])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCCCOC(=O)c1nc(-c2ccccc2)c2c(CBr)nsc2c1OC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(-c2ccccc2)c2c(Cn3ccc4ccccc43)nsc2c1O
Temperature: 25 °C
Yield: 14.1 %

Procedure:
To a solution of 3-bromomethyl-7-(2,2-dimethyl-propionyloxy)-4-phenyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (86.1 mg) in DMF (0.85 mL) at 0° C. was added indole (39.9 mg) and 60% NaH (13.6 mg). The reaction mixture was allowed to warm up to r.t. and stirred for 2 h before water (20 mL) was added. The mixture was extracted with EtOAc (4×20 mL). The combined organic phases were washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel. Eluting with 1-50% EtOAc/hexanes gave the title compound (11 mg) as a white solid: MS (m/z) 458.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH3:5])[CH3:4].[Mg:6].[CH3:7][C:8]1[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH:9]=1.S(=O)(=O)(O)O>CCOCC>[CH2:7]([Mg:6][Br:1])[CH:8]([CH3:13])[CH3:9].[CH3:7][C:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[CH:14]([CH2:2][CH:3]([CH3:5])[CH3:4])[O:15]2
Reactant: CC1=CCC(C=O)CC1
Reactant: CC(C)CBr
Reactant: [Mg]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)CC1OC2(C)CCC1CC2
Product: CC(C)C[Mg]Br
Temperature: 0 °C
Yield: 71 %

Procedure:
A solution of isobutyl magnesium bromide in ether is prepared by dropwise adding a solution of 517 grams (3.45 moles) of 1-bromo-2-methyl propane in 700 ml of dry ether to a stirred slurry of 76.5 grams of magnesium (3.15 moles) in 600 ml of dry ether under nitrogen at reflux. The resulting solution is stirred at reflux for 30 minutes. A solution of 372 grams of 4-methyl-3-cyclohexenecarboxaldehyde (3.38 moles) in 200 ml of ether is then added to the reaction mixture over a period of one hour at reflux under nitrogen. The resulting slurry is heated at reflux for 30 minutes and then cooled to 0° C. 1200 grams of 20% sulfuric acid is slowly added with external cooling over a 30-minute period. After the addition is complete, two clear layers appear. A distillation head is placed on the flask and ether is distilled from the reaction mixture at atmospheric pressure to a pot temperature of 90° C. 500 ml of water and 300 ml of isopropyl alcohol is added to the reaction mixture. Sulfuric acid (200 grams) is added slowly and the resulting solution is heated to reflux for 9 hours. At the end of this period, the reaction is cooled. 500 ml of water and 200 ml of toluene is added thereto with stirring. The phases are allowed to separate and the aqueous phase is discarded. The organic phase is washed twice with H2O with sufficient sodium carbonate added to the second wash to adjust to pH to 7-8. Distillation of the organic layer affords 220 grams (1.2 moles) of 1-methyl-3-(2-methylpropyl)-2-oxabicyclo[2.2.2]octane. Fractionation through a 1.5"×12" Goodloe column affords the pure compound (b.p. 62° C., 2.00 mm Hg pressure).
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:34])([F:33])[F:32])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[CH3:40][NH:41][CH3:42]>ClCCl.CN(C=O)C>[CH3:40][N:41]([CH2:2][C:3]1[N:7]([C:8]2[CH:9]=[C:10]([C:14]3[CH2:20][C:19](=[O:21])[NH:18][C:17]4[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[C:24]([N:26]([CH:28]([CH3:30])[CH3:29])[CH3:27])=[CH:25][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[N:6]=[N:5][CH:4]=1)[CH3:42]
Reactant: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2
Reactant: CNC
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)N(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CN(C)C)c1)=N2

Procedure:
The title compound was prepared from 4-[3-(5-hydroxymethyl-[1,2,3]triazol-1-yl)-phenyl]-7-(isopropyl-methyl-amino)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 119) (200 mg, 0.42 mmol) by reaction with thionylchloride in dichloromethane and subsequent treatment of the corresponding chloride with dimethylamine in DMF according to the method described in Example 45. Obtained as an off-white solid (80 mg, 38%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18]Br.N.CO>CC(O)=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[C:16]([Br:18])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: Nc1ccc2c(c1)ncn2Cc1ccccc1
Agent: N
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc2c(ncn2Cc2ccccc2)c1Br
Yield: 60 %

Procedure:
To a solution of 1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40 ml of AcOH was added solution of Br2 in AcOH until it produces a precipitate. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CHC13) to provide 0.90g (2.5 mmol, 60%) of the product.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([O:24]C)=[O:23])(=[O:10])=[O:9].C(N(CC)CC)C.[CH2:33]([NH2:37])[CH2:34][CH2:35][CH3:36].[Li+].[OH-]>C(#N)C>[CH2:33]([NH:37][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])[CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2ccccc12
Reactant: CCCCN
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNc1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)O
Temperature: 65 °C

Procedure:
A solution of Example 133B (0.060 g, 0.17 mmol), triethylamine (0.070 mL, 0.50 mmol), and butylamine (0.088 mL, 0.85 mmol) in anhydrous acetonitrile (0.6 mL) was heated to 200° C. for 20 minutes in a microwave reactor and concentrated. The concentrate was dissolved in 9:1 methanol/water (1 mL), treated with LiOH (25 mg, 0.6 mmol), and heated to 65° C. for 16 hours. The reaction mixture was concentrated and the concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product. MS (DCI) m/e 399 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 13.73 (br s, 1H), 10.30 (br s, 1H), 8.16 (br s, 1H), 7.88 (m, 2H), 7.57 (m, 2H), 7.49 (t, 1H), 7.34 (m, 1H), 7.26 (d, 1H), 6.72 (d, 1H), 6.59 (t, 1H), 5.87 (br s, 1H), 3.04 (t, 2H), 1.41 (quint, 2H), 1.26 (sext, 2H), 0.82 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=C[S:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].O.NN>C(O)C>[NH2:8][C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[SH:10]
Reactant: O=[N+]([O-])c1ccc2ncsc2c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc([N+](=O)[O-])cc1S
Yield: 102.2 %

Procedure:
To a stirred solution of 6-nitrobenzothiazole (30 g, 0.1665 mol) in ethanol (500 mL) is added 100% hydrazine hydrate (60.2 mL, 1.931 mol). The mixture is refluxed for 2 h at which time the solution turns red. The reaction is quenched by the addition of ice cold conc. HCl until the red color disappears. The resulting solid is filtered, washed with water (25 mL) and dried under high vacuum to give the title compound as a yellow solid (28.96 g, 84%), MS m/z 171.5 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][C:6](C(OC)=O)([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.CS(C)=O>COCCOCCOC>[CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)C1(C(=O)OC)CCC(OC)OC1
Solvent: CS(C)=O
Solvent: COCCOCCOC
Product: COC1CCC(C(=O)O)CO1

Procedure:
Dimethyl 4,4-dimethoxybutane-1,1-dicarboxylate was prepared by the Michael addition of dimethyl malonate to acrolein followed by acetalization. Subsequent hydroxymethylation with formaldehyde in the presence of potassium hydrogen carbonate gave nearly quantitatively dimethyl 1-hydroxy-5,5-dimethoxypentane-2,2-dicarboxylate. This compound rapidly underwent acid-catalyzed intramolecular cyclization in a dilute solution in benzene, aided by the favored six-membered ring formation, to yield dimethyl 6-methoxytetrahydropyran-3,3-dicarboxylate. The tetrahydropyran derivative was saponified to the free dicarboxylic acid, which was then decarboxylated in diglyme or dimethyl sulfoxide at 120°-140° C. to give 6-methoxytetrahydropyran-3-carboxylic acid as a stereoisomeric mixture in a quantitative yield. The carboxylic acid was then heated in a dilute solution in toluene in the presence of a catalytic amount of p-toluenesulfonic acid to give the desired bicyclic lactone (I). The overall yield based on acrolein was approximately 20%.
Reaction SMILES: ClC1N=C(C2SC(N3CCCC3)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[Cl:36][C:37]1[N:42]=[C:41]([CH2:43][C:44]([C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])=O)[CH:40]=[CH:39][N:38]=1.C1C(=O)N(Br)C(=O)C1.[N:69]1([C:75](=[S:77])[NH2:76])[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1>>[Cl:36][C:37]1[N:42]=[C:41]([C:43]2[S:77][C:75]([N:69]3[CH2:74][CH2:73][O:72][CH2:71][CH2:70]3)=[N:76][C:44]=2[C:46]2[C:47]([F:60])=[C:48]([NH:53][C:54](=[O:59])[O:55][CH2:56][CH:57]=[CH2:58])[CH:49]=[CH:50][C:51]=2[F:52])[CH:40]=[CH:39][N:38]=1
Reactant: NC(=S)N1CCOCC1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Agent: O=S(=O)(Nc1cccc(-c2nc(N3CCCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: C=CCOC(=O)Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6 using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2,4-difluorophenyl}carbamate (4.0 g, 10.88 mmol), NBS (2.033 g, 11.42 mmol) and 4-morpholinecarbothioamide (1.749 g, 11.97 mmol) the title compound of Step F was obtained as a yellow solid (5.11 g, 95% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.56 (br. s., 1H), 8.41-8.51 (m, 1H), 7.83 (d, J=5.9 Hz, 1H), 7.27 (t, J=8.7 Hz, 1H), 6.76 (d, J=5.3 Hz, 1H), 5.88-6.03 (m, 1H), 5.34 (d, J=17.2 Hz, 1H), 5.22 (d, J=10.1 Hz, 1H), 4.61 (d, J=5.1 Hz, 2H), 3.70-3.76 (m, 4H), 3.57 (d, J=4.4 Hz, 4H). MS (ESI): 493 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([N:11]2[CH2:16][CH2:15][CH:14]([N:17]([CH2:27][C:28]3[CH:33]=[C:32]([C:34]4[CH:61]=[CH:60][C:37]5[N:38](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:39]=[N:40][C:36]=5[CH:35]=4)[CH:31]=[CH:30][C:29]=3[F:62])[C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH:38]1[C:37]2[CH:60]=[CH:61][C:34]([C:32]3[CH:31]=[CH:30][C:29]([F:62])=[C:28]([CH:33]=3)[CH2:27][N:17]([CH:14]3[CH2:13][CH2:12][N:11]([CH:8]4[CH2:10][CH2:9]4)[CH2:16][CH2:15]3)[C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)=[CH:35][C:36]=2[N:40]=[N:39]1
Reactant: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3c(c2)nnn3C(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1F)C1CCN(C2CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(F)cc1)N(Cc1cc(-c2ccc3[nH]nnc3c2)ccc1F)C1CCN(C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (TFA, 1 mL) was added to a solution of N-(1-cyclopropyl-piperidin-4-yl)-4-fluoro-N-[2-fluoro-5-(1-trityl-1H-benzotriazol-5-yl)-benzyl]-benzamide (14 mg, 0.019 mmol) in 1 mL of dichloromethane and the resulting mixture stirred at ambient temperature overnight and then the mixture was neutralized by careful addition of 1M sodium carbonate. The layers were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered, and the volatiles were removed in vacuo to leave the crude product. Chromatography (elution with methanol/dichloromethane) provided 9 mg of the title compound. LC/MS: Retention time, 2.22 min; (M+H)=488.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([C:9]([CH3:16])([CH3:15])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[OH:17].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:17])[C:4]([C:9]([CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:16])[CH3:15])=[CH:5][C:6]=1[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: Cc1ccc(C(C)(C)CC(C)(C)C)c(O)c1C
Reactant: C=CC(=O)OC
Product: COC(=O)CCc1cc(C(C)(C)CC(C)(C)C)c(O)c(C)c1C

Procedure:
The product was obtained by reacting 2,3-dimethyl-6-(1,1,3,3-tetramethylbutyl)phenol with methyl acrylate in a similar manner as described in Example 1. The desired product was obtained as white crystals melting at 83° to 85°C (Compound 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][C:15]1([CH3:29])[C:20](=[O:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:20]2([OH:21])[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:16][C:15]2([CH3:29])[CH3:14])=[CH:3][CH:4]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
A solution of 4-bromochlorobenzene (136.6 g, 0.71 mol) in anhydrous THF (1000 mL) was cooled to −78° C., and then treated dropwise with a 1.6 M solution of n-butyllithium in hexanes (466 mL, 0.75 mol) at a rate which maintained the internal temperature below −60° C. The resulting mixture was stirred at −78° C. for 1.5 hours, during which a precipitate was observed. The resulting suspension was treated dropwise with a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (73.7 g, 0.32 mol) in anhydrous THF (400 mL) at a rate which maintained the internal temperature below −60° C. The mixture was stirred at −78° C. for 2 hours, during which a clear solution was observed. The reaction mixture was quenched with saturated ammonium chloride (300 mL) and the resulting mixture was allowed to come to room temperature. The aqueous and organic layers were separated, and the organic phase was concentrated in vacuo to yield a residue. The aqueous phase was extracted 2× with ethyl acetate (300 mL). The combined extracts were added to the residue from the original organic phase, and the resulting mixture was diluted to 1200 mL with ethyl acetate. The resulting solution was washed 2× with water (300 mL), once with brine, dried over sodium sulfate, and concentrated in vacuo to yield a residue. The residue was digested with boiling hexanes (300 mL), and the resulting suspension was cooled to room temperature. Once at the prescribed temperature, white solids were collected by filtration, and washed 2× with hexanes and then air dried to yield the title compound as a powder (93.7 g, 85% yield).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:29])([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:18]([F:21])([F:20])[F:19].[CH2:30]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C@H:41]2[CH2:46][CH2:45][C@H:44]([C:47](O)=[O:48])[CH2:43][CH2:42]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34].CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:30]([C@H:35]1[CH2:40][CH2:39][C@H:38]([C@H:41]2[CH2:42][CH2:43][C@H:44]([C:47]([O:28][C:25]3[CH:26]=[CH:27][C:22]([C:17]([F:29])([F:16])[C:18]([F:20])([F:19])[F:21])=[CH:23][CH:24]=3)=[O:48])[CH2:45][CH2:46]2)[CH2:37][CH2:36]1)[CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Oc1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(C(F)(F)C(F)(F)F)cc3)CC2)CC1

Procedure:
0.1 mol of dicyclohexylcarbodiimide (DCC) in 30 ml of CH2Cl2 is added with stirring at about 10° to a mixture of 0.1 mol of 4-(pentafluoroethyl)-phenol (preparation analogously to Bull. Chem. Soc. Japan, 57 (1984) 3361), 0.1 mol of trans-4-(trans-4-pentylcyclohexyl)-cyclohexanecarboxylic acid and 0.01 mol of dimethylamino-pyridine and 150 ml of CH2Cl2, and the mixture is then stirred for 15 hours at room temperature. It is filtered over silica gel, the solvent is evaporated and further purification gives 4-(pentafluoroethyl)-phenyl trans-4-(trans-4-pentylcyclohexyl)-cyclohexanoate.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3].C(NC1C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1)(=O)C.N12CCCN=C1CCCCC2.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:4][C:5](=[O:15])[C:6](=[N+:29]=[N-:30])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C=CCOC(=O)Cc1ccc(F)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC(=O)C(=[N+]=[N-])c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.4 %

Procedure:
(3,4-Difluoro-phenyl)acetic acid allyl ester (64 g) was dissolved in acetonitrile (400 mL) and 4-acetamidobenzenesulfonyl azide (p-ABSA, 87 g, 0.36 mol) was added and the mixture stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 58.6 mL) was added dropwise at 0° C. during 30 min. The mixture was allowed to warm up to rt (room temperature) and stirred at rt for 4-20 h (until TLC showed completion of reaction). Saturated ammonium chloride (500 mL) was added and the organic phase was separated from the water phase. The water phase was extracted with diethylether (3×200 mL) and the four combined organic phases were dried (Magnesium sulphate) and evaporated in vacuo. The resulting solid was extracted with a 50:50 mixture of diethylether/pentane (3×200 mL). The combined ether phases were evaporated in vacuo (keep temperature below 40°) and purified by flash column chromatography (silicagel, eluent: 10:90 mixture of diethylether/pentane). The yellow fractions were combined and evaporated in vacuo (keep temperature below 40°) to give 70 g diazo-(3,4-Difluoro-phenyl)acetic acid allyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[CH:38]1([NH:41][C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:40][CH2:39]1
Reactant: NC1CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(NC3CC3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and cyclopropylamine according to conditions described in general procedure C. Mp: 157-158° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.32-0.48 (m, 4 H), 1.58 (s, 6 H), 3.19-3.31 (m, 4 H), 6.34 (bs, 1 H), 6.96 (d, J=12.4, 1 H), 7.15 (d, J=8.7 Hz, 1 H), 7.34-7.42 (m, 3 H), 7.53-7.63 (m, 3H), 7.81 (d, J=8.0 Hz, 1 H), 7.95 (d, J=8.0 Hz, 1 H), 8.21-8.23 (m, 1 H), 10.40 (s, 1 H).