Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:15]([C:16]1[C:17]([CH3:19])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]=[CH:8][CH:9]=2)=[O:20])[CH3:23]
Reactant: CC(C)COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)C)c2c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a solution of 2-amino-6-isobutoxybenzonitrile (Example 41b, 16.4 g, 86.32 mmol) and ethyl acetoacetate (10.9 mL, 86.32 mmol) in anhydrous toluene (200 mL) was added SnCl4 (19.9 mL, 172.63 mmol) over a period of 15 minutes at room temperature under nitrogen. The stirred reaction mixture was then refluxed for 3.5 h under nitrogen. After it was cooled down to room temperature, the reaction solution was concentrated to remove most of the solvent under reduced pressure. The residue was re-dissolved in EtOAc (3 L) and carefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜110 mL) at 0° C. The resultant mixture was stirred at room temperature overnight. The precipitate was filtered off, and the organic layer was separated and washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 50% EtOAc in hexanes to give the title compound as a white solid (18.0 g, 69%). MS 303 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[CH3:21]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:21])[C:10](=[O:12])[CH:9]([CH3:13])[CH:8]([CH3:14])[N:7]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[C:6]=2[N:20]=1
Reactant: CC1C(=O)Nc2cnc(Cl)nc2N(C2CCCC2)C1C
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CCCC2)C1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.09 g (0.0003 mole) of (rac)-2-chloro-9-cyclopentyl-7,8-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-41), 1 mL of N,N-dimethylacetamide and 0.028 mL (0.00045 mole) of iodomethane at 0 degrees was added 0.027 g (0.00045 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.092 g of (rac)-2-chloro-9-cyclopentyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-41) as an yellow solid.
Reaction SMILES: CS(C)=O.[Cl-].[CH2:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:7]=[CH2:8].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:6]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])[CH:7]=[CH2:8]
Reactant: C=CCOCCCCO
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CCOCCCC=O
Temperature: -80 °C
Reaction time: 0.05 h

Procedure:
13 mL of DMSO (246 mmol) was gradually added to a solution prepared by dissolving oxaryl chloride (5.8 mL, 66 mmol) in 123 mL of CHCl3, which solution had been cooled to −80° C., and the mixture was stirred for three minutes. 6.8 g of 4-allyloxy-1-butanol (52 mmol) was then added to the mixture. After the solution was stirred for 15 minutes, 43 mL of triethylamine (594 mmol) was added thereto and the reaction solution was stirred for 10 hours, while the temperature of the reaction solution was allowed to return to room temperature. The reaction was quenched by adding distilled water and the CHCl3 layer was separated. The separated layer was washed with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and saturated brine and dried with anhydrous Na2SO4. The solvent was distilled away under reduced pressure, whereby pale yellow liquid was obtained (6.0 g, 90%).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10]>>[CH3:9][O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: ClCc1ccccc1
Product: COCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 10.5 gm (0.03 mol) of diamine 15, 4.0 gm (0.03 mol) of benzyl chloride, and 15 gm of MeOH were charged to the flask and heated to reflux. After 1.5 hours, GC showed 5-10% benzyl present along with amine. The reaction was allowed to reflux overnight(ca. 15 hr). GC showed the benzyl chloride consumed and some amine still present. Benzyl methyl ether was formed as a by-product of the reaction. Excess amine and other residue was removed by vigorous washing of the crude product in ether. After rotary evaporation, 10 gm (70% crude yield) of Quat 5 was obtained.
Reaction SMILES: [H-].[Na+].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][C:19](OCC)=O)=[CH:13][C:12]=1[CH3:25])C1C=CC=CC=1.ClC[C:28]1[S:29][C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]=1[CH3:33]>C1COCC1>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:24])[CH2:18][CH2:19][C:28]2[S:29][C:30]3[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=3[C:32]=2[CH3:33])=[CH:13][C:12]=1[CH3:25]
Reactant: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)c(C)c1
Reactant: Cc1c(CCl)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CCc2sc3ccccc3c2C)ccc1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
Then, to a suspension of 55% sodium hydride (123 mg, 3.07 mmol) in THF (18 mL) was added dropwise over 10 minutes under N2 atmosphere, a solution of ethyl 3-(4-benzyloxy-3-methylphenyl)-3-oxopropionate (870 mg, 2.79 mmol) in THF (5 mL). After 20 minutes, to the resultant mixture was added dropwise over 10 minutes a solution of 2-chloromethyl-3-methylbenzothiophene (548 mg, 2.79 mmol) in THF (5 mL). The mixture was heated under reflux for 25 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was heated in acetic acid (18 mL) and concentrated hydrochloric acid (4 mL) at 110° C. for 20 hours. The reaction mixture was cooled at room temperature, extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, successively. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), to give the titled compound as a yellow crystal (790 mg, yield 95%).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2=[C:9]([CH:13]=[N:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:10]=[CH:11][CH:12]=[C:7]2[C:6]([CH3:22])=[C:5]1[CH3:23])[CH:2]=[CH2:3].[CH2:24]([Mg][Cl:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[ClH:32].[CH2:1]([N:4]1[C:8]2=[C:9]([CH:13]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:10]=[CH:11][CH:12]=[C:7]2[C:6]([CH3:22])=[C:5]1[CH3:23])[CH:2]=[CH2:3]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: C=CCn1c(C)c(C)c2ccnc(C=Nc3ccc(F)cc3)c21
Product: C=CCn1c(C)c(C)c2ccnc(C(Cc3ccccc3)Nc3ccc(F)cc3)c21
Product: Cl
Yield: 33 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 135, except for using N-(1-allyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-ylmethylene)-4-fluorophenylamine prepared in Step 1 of Example 135 and benzylmagnesium chloride, the titled compound was obtained as a white solid. (Yield: 33%)
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([OH:14])[C:11]([CH2:16][CH3:17])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:27][O:28][CH2:29]Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:13][C:12]([CH3:15])([O:14][CH2:27][O:28][CH3:29])[C:11]([CH2:16][CH3:17])=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)O
Reactant: COCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1(C)OCOC
Yield: 95 %

Procedure:
To a solution mixture of 2.1 g of (1RS,4RS)-3-ethyl-4-methyl-4-hydroxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether, 2.7 g of N,N-diisopropylethylamine and 30 ml of chloroform was added under ice-cooling 1.24 ml of chloromethyl methyl ether, and the resulting mixture was allowed to react at room temperature for 8 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 2.35 g of (1RS,4RS)-3-ethyl-4-methyl-4-methoxymethoxy-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 95%
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[C:4]([O:16][CH3:17])[CH:3]=1.Cl[C:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=[O:20].N1C=CC=CC=1>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)=[O:20])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: COc1cc(F)ccc1Oc1ccccc1N
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C(=O)Nc2ccccc2Oc2ccc(F)cc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a slurry of title compound 91 (4 g, 17.15 mmol) and methyl 4-(chlorocarbonyl)benzoate (3.58 g, 18.01 mmol) in benzene (60 mL) at 0° C. was added pyridine (4.85 mL, 60.0 mmol) drop wise followed by a single crystal of DMAP. The temperature was raised to room temperature and the reaction mixture was left to stir for 1 h. The reaction mixture was filtered and the filtrate was diluted with 5% aq HCl and ethyl acetate. The organic layer was washed with 5% aq HCl, water and brine then left in the fridge over the weekend. The precipitated solid was filtered, washed with water and hexanes to afford title compound 92 (6.38 g, 94%) as an off-white solid. LRMS (ESI): (calc) 395.12. (found) 396.4 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:20](=[O:21])[CH:19]2[CH2:22][CH2:23][CH2:24][C:17](=[CH:18]2)C1=O.[Br:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH2:34])([CH3:33])[CH3:32])=[CH:29][CH:28]=1.CN1CC[O:41][CH2:40]C1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[NH:15][C:20](=[O:21])[C:19]1[CH2:18][CH2:17][CH2:24][CH2:23][C:22]=1[C:40]([NH:34][C:31]([C:30]1[CH:29]=[CH:28][C:27]([Br:26])=[CH:36][CH:35]=1)([CH3:33])[CH3:32])=[O:41]
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CN1CCOCC1
Reactant: CC(C)(N)c1ccc(Br)cc1
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (1.00 g, 2.75 mmol), 4-bromocumylamine (0.770 g, 3.60 mmol), N-methylmorpholine (0.310 g, 3.06 mmol), and benzene (15 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(4-bromocumyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.515 g, 32.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]([CH2:17][C:18]1[N:22]([CH2:23][C:24](O)=[O:25])[N:21]=[C:20]([C:27]([F:30])([F:29])[F:28])[C:19]=1[Cl:31])=[N+:15]=[N-:16].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[N:14]([CH2:17][C:18]1[N:22]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[O:25])[N:21]=[C:20]([C:27]([F:30])([F:28])[F:29])[C:19]=1[Cl:31])=[N+:15]=[N-:16]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: [N-]=[N+]=NCc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C

Procedure:
To 2.71 g (13.7 mmol) of 1-(4-Chlorophenyl)piperazine and 3.58 g (12.5 mmol) of (5-Azidomethyl-4-chloro-3-trifluoromethyl-pyrazol-1-yl)-acetic acid in 40 mL of anhydrous dimethylformamide was added 4.36 mL (31.2 mmol) of triethylamine. The solution was cooled to 0° C., and 5.21 g (13.7 mmol) of O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) was added. After 2 hours the reaction was diluted with two volumes of water, and the solvent was decanted away from the resulting oil. The oil was crystallized by dissolving in methanol and adding water in small portions. The product was isolated as a white solid by filtration: 1H NMR (DMSO-d6, 400 MHz) 7.23 (d, 2H), 6.97 (d, 2H), 5.48 (s, 2H), 4.62 (s, 2H), 3.60 (m, 4H), 3.24 (m, 2H), 3.12 (m, 2H) ppm; MS (ES) M+H expected=462.1, found=462.0.
Reaction SMILES: C(OC(N1CCCC1C1NC(C2C=CC(C3C=CC(C4NC(C5CCN(C(OC(C)(C)C)=O)C5)=NC=4)=CC=3)=CC=2)=CN=1)=O)(C)(C)C.[CH3:47][O:48][C:49](=[O:84])[NH:50][CH:51]([C:55]([N:57]1[CH:62]([C:63]2[NH:64][C:65]([C:68]3[CH:73]=[CH:72][C:71](B4OC(C)(C)C(C)(C)O4)=[CH:70][CH:69]=3)=[CH:66][N:67]=2)[CH:61]2[CH2:83][CH:58]1[CH2:59][CH2:60]2)=[O:56])[CH:52]([CH3:54])[CH3:53].[CH3:85][O:86][C:87](=[O:114])[NH:88][CH:89]([C:93]([N:95]1[CH:100]([C:101]2[NH:102][C:103]([C:106]3[CH:111]=[CH:110][C:109](Br)=[CH:108][CH:107]=3)=[CH:104][N:105]=2)[CH:99]2[CH2:113][CH:96]1[CH2:97][CH2:98]2)=[O:94])[CH:90]([CH3:92])[CH3:91].C(OC(N1CCCC1C1NC(C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)=CN=1)=O)(C)(C)C.C(OC(N1CCC(C2NC(C3C=CC(Br)=CC=3)=CN=2)C1)=O)(C)(C)C>>[CH3:85][O:86][C:87](=[O:114])[NH:88][CH:89]([C:93]([N:95]1[CH:100]([C:101]2[NH:102][C:103]([C:106]3[CH:107]=[CH:108][C:109]([C:71]4[CH:72]=[CH:73][C:68]([C:65]5[NH:64][C:63]([CH:62]6[CH:61]7[CH2:60][CH:59]([CH2:58][CH2:83]7)[N:57]6[C:55](=[O:56])[CH:51]([NH:50][C:49]([O:48][CH3:47])=[O:84])[CH:52]([CH3:53])[CH3:54])=[N:67][CH:66]=5)=[CH:69][CH:70]=4)=[CH:110][CH:111]=3)=[CH:104][N:105]=2)[CH:99]2[CH2:113][CH:96]1[CH2:97][CH2:98]2)=[O:94])[CH:90]([CH3:92])[CH3:91]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCC(c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Agent: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5C6CCC(C6)N5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
Following the procedure used to prepare compound 2-(5-{4′-[2-(1-Boc-pyrrolidin-3-yl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester, except that [2-methyl-1-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carbonyl)-propyl]-carbamic acid methyl ester and (1-{3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester were used instead of 2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR (300 MHz, CD3OD) δ 7.90-7.20 (m, 10H), 4.83-4.25 (m, 5H), 3.90-3.40 (m, 6H), 2.90-2.70 (m, 2H), 2.40-2.10 (m, 3H), 2.10-1.40 (m, 11H), 1.10-0.90 (m, 12H); m/z 791.3 (M+H)+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[N:5][N:4]=[C:3]1[C:7](=[NH:9])[NH2:8].[Cl:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]=O.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:10][C:11]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:12]=1[CH:13]1[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:21]([CH3:28])[NH:8][C:7]([C:3]2[S:2][CH:6]=[N:5][N:4]=2)=[N:9]1
Reactant: N=C(N)c1nncs1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nncs2)=NC1c1ccc(F)cc1Cl
Yield: 55 %

Procedure:
1,3,4-thiadiazole-2-carboximidamide hydrochloride (1.43 g, 8.69 mmol) was reacted with 2-chloro-4-fluorobenzaldehyde (1.38 g, 8.69 mmol) and ethyl 3-oxobutanoate (1.36 g, 10.5 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1.82 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([N:15]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:16]([CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(OC(C)(C)C)=O)[CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[ClH:1].[NH2:24][CH:20]1[CH2:21][CH2:22][CH2:23][CH:18]([C:16]([N:15]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:17])[CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC1CCCC(C(=O)N(Cc2ccccc2)Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
A 4N-hydrochloric acid/1,4-dioxane solution (4.5 ml) was added to a solution of tert-butyl 3-[(dibenzylamino)carbonyl]cyclohexanecarbamate (0.749 g, 1.773 mmol) in tetrahydrofuran (4.5 ml) and stirred overnight. The solvent was distilled off under reduced pressure, followed by replacement with toluene (twice), whereby 3-amino-N,N-dibenzylcyclohexanecarboxamide monohydrochloride (0.848 g, >99%) was obtained.
Reaction SMILES: [O-2:1].[Mg+2:2].[P:3]([O-:7])([OH:6])([OH:5])=[O:4].[NH4+:8]>O>[OH2:4].[OH2:1].[OH2:4].[OH2:4].[OH2:4].[OH2:4].[P:3]([O-:7])([O-:6])([O-:5])=[O:4].[NH4+:8].[Mg+2:2]
Reactant: [O-2]
Reactant: O=P([O-])(O)O
Agent: [Mg+2]
Agent: [NH4+]
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
U.S. Pat. No. 4,428,906 discloses a pressure-transmitting medium prepared from a mixture of borosilicate glass and a refractory powder. The refractory powder consists of magnesium oxide, ammonium dihydrogen phosphate and silica powder in the form of quartz and cristobalite. The borosilicate glass and refractory powders are mixed with water to form a slurry that is cast into the shape of a die. The refractory powder and water react at ambient temperatures to form magnesium ammonium phosphate hexahydrate which acts as a cement to bind the glass and silica powders. The phosphate decomposes to an amorphous phase upon heating to about 250° Centigrade (° C.) during drying. Further heating of the die to about 1100° C. during preheating results in conversion of the amorphous phase to magnesium pyrophosphate or, if excess magnesium oxide is present, magnesium orthophosphate.
Reaction SMILES: CC(C)([O-])C.[K+:6].[CH2:7]([O:9][CH2:10][CH2:11][SH:12])[CH3:8].[C:13](=[S:15])=[S:14]>O1CCCC1>[C:13](=[S:14])([S-:15])[S:12][CH2:11][CH2:10][O:9][CH2:7][CH3:8].[K+:6]
Reactant: CCOCCS
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCCSC(=S)[S-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.79 g potassium t-butoxide in 300 ml of anhydrous tetrahydrofuran cooled to 0° C. under a nitrogen atmosphere was added 6.42 g of 2-mercaptoethyl ethyl ether. The resulting slurry was stirred at 25° C. for 1 hour, then 4.4 ml. of carbon disulfide was added dropwise at 0° C. The resulting solution was stirred at 25° C. for 30 min., then concentrated in vacuo. Diethyl ether (300 ml) was added and the mixture was filtered, and washed with ether and dried under nitrogen to yield 12.6 g of the title compound as a yellow solid.
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])(=O)[CH3:2].[OH-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17]C=C.Cl>CO.CCOC(C)=O>[CH2:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Reactant: C=CCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCCCCSC[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.62 g (10 mmol) (S)-3-acetylsulfanyl-2-methyl-propionic acid in 20 ml MeOH is treated with 7.5 ml 4N NaOH and 1.63 g (10 mmol) 6-bromo-hex-1-ene. After being stirred for 1 h at rt the mixture is diluted with 50 ml EtOAc and acidified with 25 ml 1N HCl. The organic phase is washed with brine, dried with sodium sulfate and concentrated in vacuo to yield (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid as an oil which is used without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[I:12]I.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[C:10]([I:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Reactant: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(Cl)c(I)cc1C(=O)O
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a round-bottom flask was added a solution of 4-chloro-2-methylbenzoic acid (30.0 g, 176 mmol, 1.00 equiv) in acetic acid (300 mL). NaIO4 (19.0 g, 88.8 mmol, 0.50 equiv), I2 (49.0 g, 193 mmol, 1.10 equiv), and sulfuric acid (3 mL) were added to the reaction. The resulting mixture was stirred overnight at 110° C. After cooling to ambient temperature, the reaction was carefully quenched with 500 mL of Na2S2O3 (aq., sat.). The resulting solids were collected by filtration and then dissolved in 500 mL of ethyl acetate. The organic phase was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This resulted in 20.0 g (38%) of 4-chloro-5-iodo-2-methylbenzoic acid as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:39]=[CH:38][C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl.C(OCC)(=O)C>C(OCC)(=O)C.CO>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:38][CH:39]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCC3CCNCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.2 %

Procedure:
A mixture of tert-butyl 4-[(4-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}phenoxy)methyl]piperidine-1-carboxylate (1.5 g, 2.8 mmol) and 4 M hydrochloric acid-ethyl acetate solution (20 mL) in ethyl acetate (100 mL) and methanol (100 mL) was stirred at room temperature for 16 h. Solvent was removed in vacuo and 1 M sodium hydroxide solution was added to the mixture. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain a solid (1.1 g, 90%).