Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C@H:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)C1C=CC=CC=1.Cl.[H][H].C(N(CC)CC)C.[F:36][C:37]([F:52])([F:51])[C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[C:41](Cl)=[O:42]>CO.[Pd].O>[F:36][C:37]([F:52])([F:51])[C:38]1[CH:39]=[C:40]([C:41]([N:8]2[CH2:13][CH2:12][C@H:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[C@H:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:9]2)=[O:42])[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [H][H]
Reactant: c1ccc(CN2CC[C@H](N3CCOCC3)[C@H](c3ccccc3)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCOCC2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
Rac-cis-4-(1-benzyl-3-phenyl-piperidin-4-yl)-morpholine (1.3 g, 3.86 mmol) was dissolved in methanol (50 mL) and concentrated hydrochloric acid (0.2 mL) and palladium on charcoal (10%, 200 mg) were added. After stirring in a hydrogen atmosphere (1 bar) at room temperature overnight the mixture was filtered and the solvent was evaporated. The crude intermediate was dissolved in dichloromethane (20 mL) and triethylamine (2.69 mL, 19.3 mmol) and 3,5-bistrifluoromethyl-benzoyl chloride (0.91 mL, 5.02 mmol) were added. The reaction mixture was stirred at room temperature overnight and than diluted with 20 mL water. The organic phase was separated and the aqueous layer was extracted twice with 20 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethyl amine 80:20:1 gave the desired product (1.57 g, 83%) as off-white crystalls, MS: m/e=487.3 (M+H+).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:15][C:16]([NH2:18])=[S:17].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC1C=CC(C)=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[NH:18][C:16](=[S:17])[NH:15][C:10](=[O:12])[CH:9]=2)=[CH:3][CH:4]=1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: NC(N)=S
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccc(C)cc1
Product: O=c1cc(-c2ccncc2)[nH]c(=S)[nH]1

Procedure:
Ethyl isonicotinoylacetate (5 g, 25.89 mmol) and thiourea (5.94 g, 77.64 mmol) were suspended in anhydrous p-xylene (100 ml) with vigorous stirring. To the mixture, pyridinium p-toluenesulfonate (150 mg) was added and refluxed for 12-16 h using a Dean-Stark apparatus with continuous removal of water (0.5 ml). The reaction mixture was cooled and a dark brown solid was filtered. The collected solid was suspended in acetone (25 ml) and filtered. The acetone washed product contain trace of thiourea, which was removed by trituration with hot water (20-30 ml). The title compound was isolated by filtration. MS (m/z): 206.2 C9H7N3OS requir. 205.3. 1H-NMR (DMSO-d6): d 12.65 (bm, 2H, NH and SH), 8.71(m, 2H, pryid.), 7.66(m, 2H, Pyrid.), 6.25 (s, 1H, H-5).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]1
Reactant: COc1cccc(O[C@H]2CC[C@H](C(=O)OC)CC2)c1
Reactant: NN
Solvent: O
Product: COc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of trans-4-(3-methoxy-phenoxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.75 mmol) and hydrazine hydrate (0.035 ml, 0.73 mmol) was heated at 120° C. for 22 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and 1 M aqueous sodium hydroxide solution (50 ml). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.18 g, 92%) as white solid, which was used in the next step without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.C([Li])CCC.[C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH3:16].[CH3:23][C:24]1[C:32]([C:33](OCC)=[O:34])=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1.[Cl-].[NH4+]>C1COCC1.CCOC(C)=O>[CH3:23][C:24]1[C:32]([C:33](=[O:34])[CH2:16][C:15]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]2[N:25]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(C)nn2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn2ccccc2c1C(=O)CC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
To a solution of N,N-diisopropylethylamine (6.6 mL, 38 mmol) in THF (50 mL), n-butyllithium (1.6 mol/L in hexane solution: 24 mL, 38 mmol) was added at −40° C. After being stirred for 30 min, the mixture was cooled to −78° C. To the mixture, was added 1,1-dimethylethyl acetate (5.28 mL, 62.8 mmol) and the mixture was stirred for 40 min at −78° C. To the mixture, was added ethyl 2-methylpyrazolo[1,5-a]pyridine-3-carboxylate (3.64 g, 17.8 mmol) and the mixture was stirred for 1 h at rt. To the mixture, were added a saturated aqueous solution of ammonium chloride (300 mL) and EtOAc (300 mL) and the resulting biphasic mixture was vigorously stirred for 30 min. The organic phase was washed with brine and then dried over anhydrous magnesium sulfate. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. Column chromatography was performed to yield the title compound (1.58 g, 32%) as a pale yellow syrup. 1H NMR (300 MHz, d6-DMSO) δ: 8.78 (d, J=7.0 Hz, 1H), 8.19-8.10 (m, 1H), 7.61 (ddd, J=8.7, 7.2 and 1.1 Hz, 1H), 7.15 (td, J=7.0, 1.1 Hz, 1H), 3.91 (s, 2H), 2.61 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][C:7](=[O:22])[C:8]([NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1)([CH3:10])[CH3:9])(=[O:5])=[O:4])[CH3:2].[Br:23]Br>C(Cl)Cl.BrBr>[CH2:1]([S:3]([CH:6]([Br:23])[C:7](=[O:22])[C:8]([NH:11][C:12](=[O:21])[C:13]1[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=1)([CH3:10])[CH3:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Reactant: BrBr
Solvent: ClCCl
Product: CCS(=O)(=O)C(Br)C(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Yield: 66.6 %

Procedure:
N-(3'-Ethylthio-1',1'-dimethylacetonyl)-3,5-dichlorobenzamide (5.0 gm, 0.015 m) was taken in chloroform (200 ml) and meta-chloroperbenzoic acid (7.8 gm, 0.045 m) was added with stirring at room temperature for about 16 hours. The reaction mixture was transferred, with the use of ether (200 ml) as a rinse, to a separatory funnel. The organic solution was washed sequentially with sodium sulfite (2×100 ml), sodium bicarbonate (200 ml), water (100 ml) and brine (200 ml). The solvent was removed after drying over anhydrous sodium sulfate. Recrystallization using ethyl acetate and hexane (1:4) afforded 4.3 gm of 3-(3',5'-dichlorobenzoylamino)-2-oxo-3-methylbutyl ethyl sulfone. A portion of this sulfone (1.00 gm, 0.0027 mole) was taken in methylene chloride (50 ml) and bromine (0.13 ml, 0.003 mole) was added in one portion. Another 2-3 drops of bromine were added and the mixture was heated to reflux for about 1 hour. The solvent was removed and the resulting oil was recrystallized from hexane to obtain 800 mg of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=[C:16]([NH:29][NH2:30])[CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)#[N:32]>C(O)C>[C:31]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=[N:30][NH:29][C:16]2[CH:15]=[C:14]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:19]3[N:20]=[C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:22]=[C:18]3[N:17]=2)=[CH:35][CH:34]=1)#[N:32]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NNc1cc(N2CCOCC2)n2nc(-c3ccccc3)cc2n1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccccc4)cc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.1 %

Procedure:
There was dissolved, in ethanol (2 mL), trifluoroacetic acid salt of (7-morpholin-4-yl-2-phenyl-pyrazolo[1,5-a]pyrimidin-5-yl)-hydrazine (30.0 mg, 0.0557 mM), then 4-cyano-benzaldehyde (6.7 mg, 0.061 mM) was added to the solution and the mixture was stirred at room temperature for one hour. This reaction liquid was filtered and the resulting solid was purified by the NH-silica gel column chromatography (methanol/methylene chloride=1/20) to thus give the title compound (23.6 mg, yield: quantitative).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][NH:3]1.[H-].[Na+].Br[CH:14]([C:18]#[N:19])[C:15]([CH3:17])=[CH2:16]>CN(C)C=O>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[CH2:16][C:15]([CH3:17])=[CH:14][C:18]#[N:19]
Reactant: O=c1[nH]sc2ccccc12
Reactant: C=C(C)C(Br)C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=CC#N)Cn1sc2ccccc2c1=O
Reaction time: 0.25 h
Yield: 23 %

Procedure:
10.0 g (66 millimoles) of 2,3-dihydro-3-oxo-1,2-benzisothiazole were suspended in 140 ml of dimethylformamide, and 2.0 g (66 millimoles) of 80% strength sodium hydride were added a little at a time, while stirring thoroughly. After 15 minutes, 12.8 g (80 millimoles) of 3-bromo-2-methyl-3-cyanoprop-1-ene were slowly added dropwise, and the reaction mixture was stirred for 2 hours at 80° C. and then cooled. The solvent was distilled off under reduced pressure, the mixture was taken up in ice-water and extracted with methylene chloride, and the organic phase was washed thoroughly with H2O, dried and evaporated down. The crude product (16 g of a dark oil) was then purified by column chromatography (silica gel, mobile phase 95:5 mixture of methylene chloride and methanol). 3.5 g (23%) of 3-(2,3-dihydro-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylprop-1-ene of melting point 128°-130° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1Cl.[ClH:19].[NH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9](=[NH:10])[NH:20][OH:21])=[CH:7][C:6]=1[Cl:19]
Reactant: NO
Reactant: Cl
Reactant: N#Cc1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1

Procedure:
The subtitle compound was prepared using the product from example 29 step i) (0.60 g) which was dissolved in ethanol (20 ml) and treated with hydroxylamine hydrochloride (0.30 g) followed by potassium carbonate (0.60 g). The mixture was heated at 90 C for 2 hours, cooled and the solid filtered off. The filtrate was concentrated under reduced pressure to give a red oil. Yield 0.94 g.
Reaction SMILES: [C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH:18](O)([CH3:20])[CH3:19]>CCOCC.CN(C)C=O>[C:1]1([CH:7]([C:11]([OH:13])=[O:12])[C:8]([O:10][CH:18]([CH3:20])[CH3:19])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(C(=O)O)c1ccccc1
Reactant: CC(C)O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: CC(C)OC(=O)C(C(=O)O)c1ccccc1
Yield: 60 %

Procedure:
Phenylmalonic acid (13.5 g, 0.07 mol) in dry ether (40 mL) was treated with thionyl chloride (8.92 g, 5.4 mL, 0.07 mol) and one drop of N,N-dimethylformamide. The mixture was heated at 40°-50° C. for 3 hours. The clear solution was evaporated under reduced pressure to remove any residual thionyl chloride. The oily residue was redissolved in dry ether (40 mL), and the solution was treated with isopropyl alcohol (0.075 mol, 5.76 mL), refluxed for 2 hours and worked up as before to give the titled compound.
Reaction SMILES: C([C:5](=[C:20]([CH2:24][CH2:25][OH:26])[CH2:21][CH2:22][OH:23])[O:6][SiH:7]([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)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>CCOCC>[CH3:27][S:28]([O:26][CH2:25][CH2:24][C:20](=[CH:5][O:6][Si:7]([C:20]([CH3:24])([CH3:21])[CH3:5])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:21][CH2:22][O:23][S:28]([CH3:27])(=[O:30])=[O:29])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(O[SiH](c1ccccc1)c1ccccc1)=C(CCO)CCO
Solvent: CCOCC
Product: CC(C)(C)[Si](OC=C(CCOS(C)(=O)=O)CCOS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 9.5 h
Yield: 169.9 %

Procedure:
To a 0° C. ether (300 mL) solution of 3-(tertbutyldiphenylsilyloxymethylene)-pentane-1,5-diol (6.9 g, 19 mmol) was added methanesulfonyl chloride (4.3 mL, 56 mmol) followed by Et3 N (7.7 mL, 56 mmol). After 3-16 hours, gradually warming to ambient temperature, the reaction was washed with water, brine, dried over MgSO4, and concentrated to give the 1,5-bis(methanesulfonyloxy)-3-(tert-butyldiphenylsilyloxymethylene)-pentane 8.5 g (90%) as a colorless oil that was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]=[C:13]([F:15])[CH:14]=1)C1C=CC=CC=1.FC1C=C(O)C=C(C2(C(OCC)=O)CCOCC2)C=1>>[F:15][C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[C:11]([C:16]2([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:12]=1
Reactant: CCOC(=O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCCC1
Agent: CCOC(=O)C1(c2cc(O)cc(F)c2)CCOCC1
Product: CCOC(=O)C1(c2cc(O)cc(F)c2)CCCC1

Procedure:
The titled compound was prepared from ethyl 1-(3-benzyloxy-5-fluorophenyl)-cyclopentane-1-carboxylate according to the preparation of ethyl 4-(5-fluoro-3-hydroxyphenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[Cl:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:50][C:49]4[CH:51]=[CH:52][C:46]([Cl:45])=[CH:47][CH:48]=4)=[O:27])=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(Cl)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-chloroaniline as the aniline component. (22%, MS=504.2 (M+H))
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=O)[C:10]([CH3:16])=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:26][CH2:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[C:22]([CH:25]=1)[C:23]#[N:24].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:23]([C:22]1[CH:25]=[C:18]([NH:17][C:13]([C:11]2[C:10]([CH3:16])=[N:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH:12]=2)=[O:15])[CH:19]=[CH:20][C:21]=1[O:26][CH2:27][C:28]([CH3:30])([CH3:29])[CH3:31])#[N:24]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: Cc1nn(-c2ccc(F)cc2)cc1C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nn(-c2ccc(F)cc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
1-(4-Fluorophenyl)-3-methylpyrazole-4-carboxylic acid (1.2 g), 5-amino-2-neopentyloxybenzonitrile (1.3 g), triethylamine (1.7 g) and diethyl cyanophosphate (1.3 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (0.4 g), melting point: 181–182° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:20])=[N:4][N:5]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[N:13]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>CCCCCC.CCOC(C)=O>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]([OH:27])[C:2]2[C:3]([CH3:20])=[N:4][N:5]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[N:13]=3)[C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1c(I)c(C)nn1-c1ccnc(OC)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1ccnc(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.3 using ethyl 4-iodo-1-(2-methoxypyrimidin-4-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 59.3) and 4-chlorobenzaldehyde at RT for 60 min. tR: 5.20 min (HPLC 1); tR: 1.18 min (LC-MS 2); ESI-MS: 403 [M+H]+ (LC-MS 2); Rf=0.44 (hexane/EtOAc 1:1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:18]2[CH:19]=[N:20][NH:21][CH:22]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O>[NH:20]1[CH:19]=[C:18]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:22]=[N:21]1
Reactant: O=Cc1ccccc1Br
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1-c1cn[nH]c1
Temperature: 100 °C
Yield: 39.4 %

Procedure:
To a solution of 2-bromobenzaldehyde (300 mg, 1.62 mmol) in DMF (10 mL) are added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (470 mg, 2.43 mmol), Pd(PPh3)4 (190 mg, 0.16 mmol) and 2M Na2CO3 (0.50 mL) at room temperature. The solution is heated to 100° C. for 1 hour in a microwave reactor, cooled and poured into water and EtOAc. Layers are separated and the aqueous phase extracted with EtOAc (1×10 mL). The combined organics are dried (MgSO4), filtered and are concentrated to give the crude product which is purified via flash chromatography (12 g silica gel, 0-10% MeOH/CH2Cl2). The product-containing fractions are combined and concentrated to give 2-(1H-pyrazol-4-yl)-benzaldehyde (110 mg, 39%) which is used without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH3:6][N:7]([CH3:9])[CH3:8]>>[Cl-:2].[O:5]1[CH2:4][CH:3]1[CH2:1][N+:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: CN(C)C
Reactant: ClCC1CO1
Product: C[N+](C)(C)CC1CO1
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
A one-liter flask equipped with gas sparger, mechanical stirrer, thermometer and an aqueous acid trap was charged with epichlorohydrin (55.2 grams, 6.0 mol) and placed in an isothermal bath at 19° C. Trimethylamine gas (119.5 grams, 2.0 mol) was then sparged into the epichlorohydrin over a period of 3 hours. The temperature was maintained below 23° C. The solution was stirred for an additional 30 minutes and the precipitate collected by filtration. The crystalline product was washed with diethylether and vacuum dried to afford 262.2 grams of 2,3-epoxypropyltrimethylammonium chloride.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:3]([C:5]1[CH:6]=[C:7]([OH:12])[CH:8]=[C:9]([CH:11]=1)[OH:10])[CH3:4].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]=O>C(O)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:24][C:8]2[C:7]([OH:12])=[CH:6][C:5]([CH:3]([CH:2]([CH3:1])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:4])=[CH:11][C:9]=2[OH:10])[CH2:19][CH2:20]1
Reactant: C1COCCN1
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: C=O
Solvent: CCO
Product: CCCCCC(C)C(C)c1cc(O)c(CN2CCOCC2)c(O)c1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
2.36 g (0.01 mole) of 5-(3-methyl-2-octyl)resorcinol was dissolved in 40 ml of absolute ethanol and 0.73 g (0.01 mole) of morpholine was added. The solution was cooled in ice/salt bath and 0.91 g (0.018 mole) of formaldehyde solution (37.2% w/w) was added. The temperature was kept at 5°C for 2 hours. The mixture was then slowly allowed to rise to room temperature overnight. The alcohol was removed in vacuo and the residue was dissolved in ether. The ether extract was washed with water, dried and evaporated to leave a gum which was purified by chromatography on activated magnesium silicate and eluted with 5% methanol/ether mixture. Fractions showing one spot on thin layer chromatograph (10% methanol/chloroform) were combined and evaporated to leave 2.5 g (74%) of a gum. Nmr spectra was in agreement with the structure.
Reaction SMILES: C(NC1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.[CH2:24]([N:26]([CH2:47][CH3:48])[C:27]1[CH:32]=[C:31]([O:33]C)[CH:30]=[CH:29][C:28]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45]C)[CH:41]=2)[CH2:36]1)[CH3:25]>>[CH2:47]([N:26]([CH2:24][CH3:25])[C:27]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=1[CH:35]1[CH2:44][CH2:43][C:42]2[CH:41]=[C:40]([OH:45])[CH:39]=[CH:38][C:37]=2[CH2:36]1)[CH3:48]
Reactant: CCN(CC)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(CC)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 79.5 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Example 36, diethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (288 mg) was used according to an analogous synthetic method to Example 111 described below to proide the title compound (210 mg).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:13]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)[N:12]=1)=[O:15])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cccc(Cc2ccc(F)cc2)n1
Product: CC(C)C[C@H](NC(=O)c1cccc(Cc2ccc(F)cc2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(4-fluorobenzyl)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=344.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([OH:12])([C:4]#[C:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:3].ClC1C=C(C2C=CC=CC=2C(OO)=[O:23])C=CC=1>ClCCl>[OH:12][C:2]([CH3:1])([CH3:3])[C:4](=[O:23])[CH:5]=[CH:6][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C(OO)c1ccccc1-c1cccc(Cl)c1
Reactant: CC(C)(O)C#CCN1CCCC1
Solvent: ClCCl
Product: CC(C)(O)C(=O)C=CN1CCCC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2-methyl-5-(pyrrolidin-1-yl)-pent-3-yn-2-ol (0.25 g) in dichloromethane (6 ml) was added in small portions 3-chlorophenylperoxybenzoic acid (0.285 g) over a period of about 2 minutes. After the reaction was stirred at 0° C. for 5 minutes, the mixture was passed over 20 weight equivalents of basic alumina (Brockmann Grade I, 150 mesh) and eluted with 5% methanol in dichloromethane. All fractions containing the desired amine N-oxide were combined and evaporated to near dryness in vacuo. The resulting residue was dissolved in methanol (20 ml) and heated to reflux temperatures for 7 hours. The solvent was then removed in vacuo and the residue was chromatographed over silica gel (50% ethyl acetate in hexanes was used as the eluant) to provide the desired product as an amber solid. MS(+ES), m/z: 184 (M+H)+.