Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[F:7][C:8]([F:12])([F:11])[CH2:9]I.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:9][C:8]([F:12])([F:11])[F:7])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1cc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-1-H-pyrazole (9.4 mmol, 1.38 g), 1,1,1-trifluoro-2-iodo-ethane (28.2 mmol, 2.75 mL), and cesium carbonate (14.1 mmol, 4.58 g) were combined in DMF (10 mL) and stirred at room temperature for overnight. The resulting mixture was subjected to standard aqueous workup to afford the title compound which was used crude in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][O:14][C:15]1[C:22]([CH3:23])=[C:21]([CH3:24])[C:20]([O:25][CH3:26])=[C:19]([CH3:27])[C:16]=1[CH2:17]Br>C(OCC)C.O>[CH3:26][O:25][C:20]1[C:21]([CH3:24])=[C:22]([CH3:23])[C:15]([O:14][CH3:13])=[C:16]([CH3:17])[C:19]=1[CH2:27][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)c(OC)c(CBr)c1C
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: COc1c(C)c(C)c(OC)c(Cc2cccnc2)c1C
Yield: 85.7 %

Procedure:
A solution of 15.5 g (98.1 mmol) of 3-bromopyridine in 200 ml of ethyl ether was cooled to -78° C., to which 61.3 ml (98.1 mmol) of n-butyllithium (1.6M hexane solution) was added dropwise. For 20 minutes after completion of the addition, the mixture was stirred at the same temperature, and then a solution of 26.8 g (98.1 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzyl bromide in 100 ml of ethyl ether was added dropwise. After stirring at -78° C. to room temperature for 1 hour, the reaction mixture was diluted with water and extracted with ethyl acetate. Then the extract was extracted reversely with 2N-hydrochloric acid, and the water layer was made weakly alkaline with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified with silica gel column chromatography (ethyl acetate), to give 22.8 g (85.8%) of 3-(2,5-dimethoxy- 3,4,6-trimethylbenzyl)pyridine.
Reaction SMILES: C(OC(/N=N/C(=O)OC(C)C)=O)(C)C.[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:29])[C:21]=1[N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49](=[O:52])([SH:51])[CH3:50]>C1COCC1.C(OC(=O)C)C>[C:49](=[O:52])([S:51][CH:25]1[CH2:26][CH2:27][N:22]([C:21]2[C:20]([F:29])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:15])[CH2:23][CH2:24]1)[CH3:50]
Reactant: OC1CCN(c2c(F)cncc2Cl)CC1
Reactant: CC(=O)S
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)SC1CCN(c2c(F)cncc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
isopropyl (NE)-N-isopropoxycarbonyliminocarbamate (723.1 mg, 3.576 mmol) was added dropwise to a solution of 1-(3-chloro-5-fluoro-4-pyridyl)piperidin-4-ol (750 mg, 3.251 mmol) and Triphenylphosphine (937.9 mg, 828.5 μL, 3.576 mmol) in THF at −20° C. After stirring for 15 mins, ethanethioic S-acid (272.2 mg, 255.6 μL, 3.576 mmol) was added, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The mixture was then diluted with ethylacetate (30 ml), washed twice with water (20 ml) and with brine. The organic layer was dried with MgSO4 and concentrated in vacuo to a yellow solid that was purified by column chromatography eluting with 5/95 ether/pet ether to elute side products and then 10/90 ether/pet ether. The relevant fractions were combined and concentrated in vacuo to afford S-(1-(3-chloro-5-fluoropyridin-4-yl)piperidin-4-yl) ethanethioate as a green solid. MS (ES+) 289.0.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1[CH:14]2[CH2:15][C:16](=O)[CH:12]([CH2:13]2)[CH2:11]1.C([N-]C(C)C)(C)C.[Li+]>C1C=CC=CC=1.O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH2:9][C:1]1[C:2]2[C:3]([N:4]=[C:11]3[C:10]=1[CH:14]1[CH2:13][CH:12]3[CH2:16][CH2:15]1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: N#Cc1ccccc1N
Reactant: O=C1CC2CCC1C2
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Nc1c2c(nc3ccccc13)C1CCC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
A solution of anthranilonitrile (3.6 g, 30.0 mmole), norcamphor (3.3 g, 30.0 mmole) and para-toluenesulfonic acid (50 mg) in benzene (50 ml) was heated to reflux using a Dean Stark apparatus. After heating for 18 hours, the reaction mixture was then cooled (25° C.) and the separated water (about 1.5 ml) was withdrawn. The excess benzene was then removed under vacuum (1 mm Hg, 15 minutes). The oily residue thus obtained was dissolved in tetrahydrofuran (THF, 10 ml) and was cooled to 0° C. and a solution of lithium diisopropylamide in THF (1M, 36 ml, 36 mmole) was then added. This reaction mixture was then stirred at 0° C. for 3 hours. At the end of this period, the reaction mixture was quenched with 40 ml of water and was extracted with methylene chloride (200 ml). The resulting organic phase was washed with water (2×50 ml) and dried (anhydrous MgSO4). The methylene chloride was removed under vaccum to afford a residue which was loaded on a silica gel flash chromatography column. Elution with 5% methanol in methylene chloride containing 1% triethylamine afforded the title compound 1.6 g, 25%) as an oil which solidified on standing (m.p. 185°-186° C.). 1H-NMR (CDCl3, 300 MHz, δ): 2H, m, 1.22-1.42 ppm; 1H, d, 1.64 ppm (J=7.0 Hz); 1H, d, 1.86 ppm (J=6.0 Hz); 2H, m, 1.9-2.04 ppm; 2H, bd, 3.46 ppm; 2H, bs, 4.49 ppm; 1H, t, 7.38 ppm (J=6.0 Hz); 1H, t, 7.55 ppm (J=6.0 Hz); 1H, d, 7.67 ppm (J=6.0 Hz); 1H, d, 7.92 ppm (J=6.0 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1O
Solvent: CC(=O)O
Product: Cc1cccc([N+](=O)[O-])c1O
Temperature: 0 °C

Procedure:
To an ice-cooled solution of 2-methylphenol (10.8 g, 0.1-mmol) in acetic acid, fuming nitric acid (6.3 g) was slowly added with stirring to start reaction. The reaction mixture was stirred at a temperature of 20° C. or below for 1 h and thereafter poured into ice water. The reaction product was extracted with ethyl acetate and the extracted layer was washed with water, saturated sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride in the order written. Thereafter, the washed layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography with a benzene-ethyl acetate mixture used as eluant, thereby giving the desired compound, 2-methyl-6-nitrophenol, in an amount of 1.3 g.
Reaction SMILES: [N:1]1C=CC=CC=1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: c1ccncc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
The optically pure resin-bound secondary amine resin (from Step C) was swelled in DCM (200 mL). To the suspension was added pyridine (3.19 g) and then 4-bromophenylsulfonyl chloride (5.1 g, 20.0 millimole). The suspension was shaken overnight. The resin was filtered and washed with 3 portions of DCM, 3 portions of methanol, 3 portions of DCM, and 3 portions of methanol. The resin was dried in vacuo overnight.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:8]=1)=[O:5].[CH:26](=O)[CH2:27][CH3:28].C(O)(=O)C>C1COCC1>[F:25][C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:26][CH2:27][CH3:28])[CH2:18][CH2:19]2)[N:8]=1)=[O:5]
Reactant: CCC=O
Reactant: O=C(Nc1cccc(OC2CCNCC2)n1)c1c(F)cc(F)cc1F
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCN1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Yield: 68.7 %

Procedure:
Combine 2,4,6-trifluoro-N-[6-(piperidin-4-yloxy)pyridin-2-yl]-benzamide (example 84, 250 mg, 0.71 mmol), propionaldehyde (124 mg, 2.14 mmol), acetic acid (85 mg, 1.42 mmol), molecular sieve 4 Å (0.4 g) and THF (6 mL), stir for 15 min. Then add NaBH(tri-acetate) portionwise and stir for 3 hr. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 5% 2M NH3-methanol in methylene dichloride provides 192 mg (69%) of the title compound: mass spectrum (ion spray): m/z=394.1 (M+1); 1H NMR (CDCl3, ppm): 8.00 (s, br, 1H), 7.84 (d, br, 1H), 7.64 (t, 1H), 6.78 (m, 2H), 6.52 (d, 1H), 4.94 (m, 1H), 2.75 (m, 2H), 2.32 (m, 4H), 2.04 (m, 2H), 1.85 (m, 2H), 1.55 (m, 2H), 0.92 (t, 3H). Mono-hydrochloride salt: Anal calcd for C20H22F3N3O2.HCl.0.25H2O: C, 55.30; H, 5.45; N, 9.67. Found: C, 55.13; H, 5.36; N, 9.61.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4](C)[CH:5]=O.[CH:8]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])OCC.C([O-])([O-])=O.[Na+].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:16]([O:15][CH:8]([O:12][CH2:13][CH3:14])[CH:4]([CH3:5])[CH2:3][CH2:2][Cl:1])[CH3:17]
Reactant: CC(C=O)CCCl
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(OCC)C(C)CCCl
Temperature: 45 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 4-chloro-2-methylbutyraldehyde (4.8 g, 0.040 moles), triethyl orthoformate (6.48 g, 0.044 moles), ethyl alcohol (3.0 g), and p-toluenesulfonic acid monohydrate (0.0144 g, 0.000757 moles) was stirred at 45° C. overnight under an argon atmosphere. Next, after cooling to room temperature, Na2CO3 (0.40 g) was added and the mixture was stirred for 15 min. The reaction mixture was filtered and ethyl alcohol and residual triethyl orthoformate were distilled off under reduced pressure. The residue was subjected to fractional vacuum distillation giving 3.2 g of pure 4-chloro-2-methylbutyraldehyde diethyl acetal. NMR (d6-DMSO): 0.85 ppm (d, —CH3, 3H) 1.13 ppm (m, —CH3, 6H), 1.52 ppm (m, —CH—, 1H), 1.87 ppm (m, —CH2CH2Cl, 2H), 3.35-3.75 ppm (bm, —OCH2CH3, 4H, and —CH2Cl, 2H), 4.22 ppm (d, —CH acetal, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH3:18].C(O)C>C(OCC)(=O)C>[NH2:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Reactant: N
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Twent-six grams (0.096m) of crude 4-chloro-3,5-dinitrobenzotrifluoride, 150 ml. of liquid ammonia and 150 ml. of 2B ethanol were heated in a sealed autoclave at 100° C. for about 4 hours. After cooling and venting, the reaction mixture was taken up in ethyl acetate. The ethyl acetate phase was washed with water. The ethyl acetate solution was dried and evaporated in vacuo to yield crude 4-amino-3,5-dinitrobenzotrifluoride.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:8][CH2:9][O:10][C:11]([C:13]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[C:17]([C:26](O)=[O:27])=[C:16]([CH3:29])[NH:15][C:14]=2[CH3:30])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:37]1[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN=C=NCCCN(C)C.Cl.CN(C=O)C>ClCCl>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][O:10][C:11](=[O:12])[C:13]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[C:17]([C:26]([N:37]3[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:27])[C:16]([CH3:29])=[N:15][C:14]=2[CH3:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCC(c2ccccc2)c2ccccc2)=C(C)N1
Reactant: C1CNCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C)c(C(=O)N2CCCNCC2)c(-c2cccc(Cl)c2)c1C(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
200 mg (0.398 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 120 mg (1.20 mmol) of homopiperazine and 230 mg (1.20 mmol) of WSC hydrochloride were stirred in 6 ml of dichloromethane at room temperature overnight. 0.8 ml of DMF was added and stirred at 60° C. for 5 hours. After concentration under reduced pressure, chloroform was added. After being washed with saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained substance was dissolved in 5 ml of dichloromethane. 2 ml of trifluoroacetate was added and stirred at room temperature for 30 minutes. After concentration under reduced pressure, ethyl acetate was added and the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the thin layer silica gel chromatography (dichloromethane/methanol=9/1) to obtain the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C@H:2]([CH3:4])[OH:3].N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CN(C=O)C.O>[Si:14]([O:3][C@@H:2]([CH3:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CCOC(=O)[C@H](C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (S)-ethyl lactate (11.8 g, 100 mmol) in DMF (50 mL) was added imidazole (10.2 g, 150 mmol). The mixture was cooled in an ice bath and tert-butyldimethylsilyl chloride (15.8 g, 105 mmol) was added in three portions, at intervals of 30 min between each addition. The reaction mixture was stirred overnight. The reaction mixture was diluted with water (30 mL) and extracted with Et2O (50 mL×2). The combined extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was distilled under vacuum (bp 70-78° C., 0.5 mmHg) to afford 22.07 g (95%) of (S)-ethyl 2-(tert-butyldimethylsilyloxy)propanoate: 1H NMR (400 MHz, CHLOROFORM-d) δ 4.32 (q, J=6.6 Hz, 1H), 4.11-4.25 (m, 2H), 1.40 (d, J=6.6 Hz, 3H), 1.29 (t, J=7.1 Hz, 3H), 0.93 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH:13]1[C:18]([CH:19]=O)=[CH:17][C:16]2[O:21][CH2:22][O:23][C:15]=2[CH:14]=1.Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7](=[CH:19][C:18]1[CH:13]=[CH:14][C:15]3[O:23][CH2:22][O:21][C:16]=3[CH:17]=1)[CH2:6][CH2:5]2
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: O=C1C(=Cc2ccc3c(c2)OCO3)CCc2cc(O)ccc21
Temperature: 25 °C
Yield: 89.8 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and piperonal 1.11 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for 0.5 hours and cooled to room temperature, and the precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 1.63 g.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20]>CN(C)C=O.O>[I:1][C:2]1[N:3]([CH:19]([CH3:21])[CH3:20])[N:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CC(C)I
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnn(C(C)C)c1I
Temperature: 60 °C
Reaction time: 2 h
Yield: 18.6 %

Procedure:
To a solution of ethyl 3-iodopyrazole-4-carboxylate (1.58 g, 5.94 mmol, Truong; et al. Bioorg. Med. Chem. Lett., 19, 4920 (2009)) in 20 mL N,N-dimethylformamide was added cesium carbonate (3.87 g, 11.9 mmol) and 2-iodopropane (0.89 mL, 8.90 mmol). The mixture was stirred 2 hours at 60° C. and then cooled to ambient temperature. The reaction mixture was diluted with 150 mL water and extracted with 2×100 mL diethyl ether. The combined organics were washed with 50 mL brine, dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by flash chromatography (7-60% ethyl acetate/heptane gradient, 50 g silica) to yield 340 mg of ethyl 5-iodo-1-isopropyl-1H-pyrazole-4-carboxylate as a clear oil which crystallized on standing and 740 mg of ethyl 3-iodo-1-isopropyl-1H-pyrazole-4-carboxylate as a clear oil.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][NH:6][C:7]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])=S.CN(C)C=O>C(#N)C>[C:2]([NH:3][C:7]([NH:6][CH3:5])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:1]
Reactant: CNC(=S)NCCSCc1[nH]cnc1C
Reactant: N#CN
Agent: [Pb]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Reaction time: 24 h

Procedure:
Lead cyanamide (3.0 g.) was added to a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]thiourea (2.44 g.) in acetonitrile (50 ml.). Dimethylformamide (b 20 ml.) was added subsequently and the suspension was heated under reflux, with stirring, for 24 hours. Filtration, followed by concentration under reduced pressure and purification of the product by chromatography on a column of silica gel with acetonitrile as eluant and recrystallisation from the same solvent afforded N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)- methylthio)ethyl]guanidine, m.p. 139°-141°. (Found: C, 47.3; H, 6.6; N, 33.4; S, 12.6. C10N16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:58][O:59][CH2:60][CH2:61]Br>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:61][CH2:60][O:59][CH3:58])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in DMF (0.2 M) was added cesium carbonate (1.3 eq.) and 2-bromoethyl methyl ether (1.6 eq.). The reaction was heated to 80° C. and stirred for 3 h. After cooling to rt, the reaction was diluted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 50%→65% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(OCC)(=O)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[O:23]([C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(Oc2cnc(OC3CN4CCC3CC4)nc2)cc1
Yield: 93.3 %

Procedure:
The product of Example 29A (284 mg, 1.0 mmol) was treated with phenol (Aldrich, 188 mg, 2 mmol) according to the procedure of Example 14C. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.15) as an oil (42 mg, yield, 14%). The free base of the title compound (42 mg, 0.14 mmol) in ethyl acetate:MeOH (3 mL, 10:1) was treated with fumaric acid (18 mg, 0.15 mmol) at room temperature for 10 hours. The title compound was obtained as a solid (22 mg, 36%). 1H NMR (MeOH-d4, 300 MHz) δ 1.84–2.18 (m, 3H), 2.25–2.38 (m, 1H), 2.50–2.58 (m, 1H), 3.23–3.44 (m, 5H), 3.80–3.88 (m, 1H), 5.32 (m, 1H), 6.69 (s, 2.5H), 7.00–7.06(m, 2H), 7.15–7.20 (m, 2H), 8.39 (s, 2H) ppm. MS (DCl/NH3) m/z 298 (M+H)+. Anal. Calculated for C17H19N3O2.1.26C4H4O4: C, 59.67; H 5.46; N, 9.47. Found: C, 59.43; N, 9.51.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Cl:32]N1C(=O)CCC1=O>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([Cl:32])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(Cl)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (116 mg, 0.310 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., cooled to −78° C. and N-chlorosuccinimide (1.5 equiv) in THF (3 mL) was added dropwise. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl chloride, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (73 mg, 57%): 1H NMR (CDCl3, 600 MHz) 7.29-7.26 (m, 2H), 7.18-7.17 (m, 3H), 6.82 (s, 1H), 4.71 (t, 1H, J=7.2 Hz), 2.60 (t, 2H, J=7.8 Hz), 1.88-1.80 (m, 2H), 1.62-1.60 (m, 2H), 1.43-1.35 (m, 6H), 0.89 (s, 9H), 0.09 (s, 3H), −0.01 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 165.6, 143.6, 136.9, 129.3, 129.1, 126.5, 122.9, 69.5, 37.0, 36.8, 32.3, 29.9, 29.9, 26.6, 19.1, −4.2, −4.3.