Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[C:18]([Br:26])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([Br:26])[CH:17]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)Nc1ccc(C(=O)O)c(Br)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of (2S,4R)-2-(3-bromo-4-methoxycarbonyl-phenylcarbamoyl)-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg, 0.898 mmol) in MeOH (9 mL) was added a 2N aqueous NaOH solution (1.78 mL, 3.59 mmol). The reaction mixture was stirred at RT for 20 h and then evaporated under reduced pressure. The residue was taken up in water and the aqueous phase was acidified (pH 2 to 3) by adding 0.1N aqueous HCl. The resulting suspension was extracted with EtOAc (4×) and the combined organics were concentrated under reduced pressure to afford the crude title compound as a pale yellow solid. This product was used in the next reaction step without further purification. MS (LC/MS): 454 [M+Na]+, 374 [MH−tBu]+, 330 [MH−Boc]+; tR (HPLC conditions b): 3.41 min.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[C:15]([N:25]1[CH2:28][C:27]([C:30]2[CH:46]=[CH:45][C:33]([NH:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])=[CH:32][C:31]=2[F:47])(O)[CH2:26]1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C(Cl)Cl>[C:15]([N:25]1[CH2:26][CH:27]([C:30]2[CH:46]=[CH:45][C:33]([NH:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])=[CH:32][C:31]=2[F:47])[CH2:28]1)([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16]
Reactant: O=C(Nc1ccc(C2(O)CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(C2CN(C(=O)OCc3ccccc3)C2)c(F)c1)OCc1ccccc1
Reaction time: 48 h

Procedure:
Triethylsilane (30 mL) and trifluoroacetic acid (12 mL) were added to a solution of N-carbobenzyloxy-3-(N-carbobenzyloxy-3-fluoroanilin-4-yl)-3-hydroxyazetidine (Example 81, Step 3, 4.3 g, 9.55 mmol) in methylene chloride (40 mL) and stirred for 2 days. Removal of the solvents at 45°/0.75 mm gave an amber oil. Chromatography over silica gel (150 g, 40-60 μm) eluting with 1-3% methanol-chloroform yielded the title compound as a solid, m.p. 95°.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].CN(CCN(C)C)C.[I:30]I>C1COCC1>[F:13][C:10]1[C:9]([I:30])=[C:8]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:7]([F:6])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1F
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)ccc(F)c1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
nBuLi (5.67 mL, 14.2 mmol) was added to a solution of tert-butyl (2,5-difluorophenyl)carbamate (1.08 g, 4.73 mmol) and TMEDA (2.14 mL, 14.2 mmol) in THF (21.6 mL) at −78° C. over 20 minutes, ensuring the internal temperature remained below −70° C. The resulting solution was stirred at −78° C. for 1 h. Iodine (3.60 g, 14.2 mmol) in THF (10 mL) was added dropwise over 30 min, also ensuring the internal temperature remained below −70° C. The resulting reaction was stirred for 1 h at −78° C., The reaction was quenched at −78° C. with water and the reaction warmed to room temperature. 10% Sodium thiosulfate was added until the iodine color dissipated and the mixture was then extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried (MgSO4), filtered and concentrated. The crude material was purified on silica gel, eluting 0-60% EtOAc in hexanes over 28 minutes to afford tert-butyl (3,6-difluoro-2-iodophenyl)carbamate (1.14 g, 3.20 mmol) as a white crystalline solid. MS (ESI): m/z=300.2 (M+H-[t-Bu]).
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[S:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=2)=[N:8]1.[F:25][C:26]1[CH:27]=[C:28]([CH:40]=[CH:41][C:42]=1[F:43])[CH2:29][N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36](O)=[O:37])[C:31]1=[O:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C)C=O.C(N(CC)C(C)C)(C)C>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>[NH:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]2[S:20][C:19]([CH2:21][NH:22][C:36]([C:32]3[C:31](=[O:39])[N:30]([CH2:29][C:28]4[CH:40]=[CH:41][C:42]([F:43])=[C:26]([F:25])[CH:27]=4)[CH:35]=[CH:34][CH:33]=3)=[O:37])=[CH:18][CH:17]=2)=[N:8]1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(CN)s2)c2cccnc21
Reactant: O=C(O)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCc1ccc(-c2n[nH]c3ncccc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
C-{5-[1-(2-Trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-thiophen-2-yl}-methylamine (23 mg, 0.000064 mol), 1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (2.0E1 mg, 0.000075 mol) and HATU (44 mg, 0.00012 mol; Applied Biosystems) were dissolved in N,N-dimethylformamide (1.25 mL, 0.0161 mol; Acros). To this was added N,N-diisopropylethylamine (56 uL, 0.00032 mol; Aldrich) and the reaction was stirred for 1 hour at room temperature. The reaction was diluted with 5% citric acid in water, then extracted with ethyl acetate. Saturated sodium chloride was added to aid separation. The organic layer was washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated to yield the crude title compound. MS m/z=608.34 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:19])([F:18])[F:17])[C@H:13]([CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]([F:19])([F:17])[F:18])[C@H:13]([CH2:20][NH2:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1C[C@@H](CN2C(=O)c3ccccc3C2=O)[C@H](C(F)(F)F)C1
Agent: NN
Solvent: CO
Solvent: O
Product: NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.3 %

Procedure:
In 150 ml of methanol, is dissolved 9.33 g (21.6 mmol) of trans-1-benzyloxycarbonyl-3-phthalimidomethyl-4-trifluoromethylpyrrolidine. To the above solution, is added 2.1 ml (43.2 mmol) of hydrazine monohydrate, and the mixture is stirred at room temperature for 12 hours. The resulting precipitate is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in dichloromethane and washed with water. The washed solution is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (elusion solvent; chloroform/methanol (100/2→100/5)) to give 5.89 g of the objective substance as a yellow oily matter (yield 90.3%).
Reaction SMILES: [Cl:1][CH:2]=[CH:3]Cl.N1CCCCC1.[C:11]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1)#[CH:12]>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.[Cu]I.C1COCC1>[Cl:1]/[CH:2]=[CH:3]/[C:12]#[C:11][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(C=O)cc1
Reactant: ClC=CCl
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: O=Cc1ccc(C#C/C=C/Cl)cc1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 59 %

Procedure:
1,2-Dichloroethylene (3.0 mL), tetrakis(triphenylphosphine)palladium (0.44 g), CuI (73 mg) and piperidine (1.1 mL) were added to a THF (20 mL) solution of 4-ethynylbenzaldehyde (1.0 g), and the mixture was stirred for 22.5 hours at room temperature in a nitrogen atmosphere. IPE was added, the insolubles were filtered out, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by OH type silica gel column chromatography (hexane/ethyl acetate/chloroform=9/1/1) to obtain 4-((E)-4-chlorobut-3-en-1-yn-1-yl)benzaldehyde (light brown solid) (0.87 g, 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[N+:10]([C:13]1[C:14]([C:18](O)=O)=[N:15][NH:16][CH:17]=1)([O-:12])=[O:11].[OH-].[NH4+]>Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:18]([C:14]3[C:13]([N+:10]([O-:12])=[O:11])=[CH:17][NH:16][N:15]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-benzene-1,2-diamine (500 mg) in hydrochloric acid (4N) was treated with 4-nitro-pyrazole-3-carboxylic acid (826 mg) then heated at reflux temperature, under nitrogen. The reaction mixture was cooled to room temperature when the pH was adjusted to 8 by addition of ammonium hydroxide and the mixture was extracted with ethyl acetate. The extracts were evaporated to give 5-chloro-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole. (b) 5,6-dichloro-2-(4-nitro-1H-pyrazol -3-yl)-1H-benzoimidazole
Reaction SMILES: C(OP([CH:9]([F:11])[F:10])(=O)OCC)C.C([N-]C(C)C)(C)C.[Li+].[CH3:20][O:21][C:22]1[CH:39]=[CH:38][C:37]2[C@@H:36]3[C@H:27]([C@H:28]4[C@@:32]([CH2:34][CH2:35]3)([CH3:33])[C:31](=O)[CH:30]=[CH:29]4)[CH2:26][CH2:25][C:24]=2[CH:23]=1>O1CCCC1>[F:11][C:9]([F:10])=[C:31]1[CH:30]=[CH:29][C@H:28]2[C@H:27]3[C@H:36]([CH2:35][CH2:34][C@:32]12[CH3:33])[C:37]1[CH:38]=[CH:39][C:22]([O:21][CH3:20])=[CH:23][C:24]=1[CH2:25][CH2:26]3
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Reactant: CCOP(=O)(OCC)C(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=C(F)F)C=C[C@@H]12
Reaction time: 1 h
Yield: 47.8 %

Procedure:
A solution of 9.4 g of diethyl-(difluoromethyl)-phosphonate in 150 ml of tetrahydrofuran is slowly mixed with 25 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 5.6 g of 3-methoxy-estra-1,3,5(10),15-tetraen-17-one in 173 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 6 hours. For working-up, half the volume is concentrated by evaporation in a vacuum, diluted with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 3.0 g of 17-difluoromethylene-3-methoxy-estra -1,3,5(10),15-tetraene is obtained as colorless crystals with a melting point of 122-123° C., [α]D22 -120.9° (c=0.515% in pyridine).
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[O:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20].BrC(C)C>CS(C)=O>[CH3:22][O:21][C:19]([C:9]1[O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[C:8]=1[O:7][CH:2]([CH3:3])[CH3:1])=[O:20]
Reactant: COC(=O)c1oc2ccc(OC)cc2c1O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)Br
Solvent: CS(C)=O
Product: COC(=O)c1oc2ccc(OC)cc2c1OC(C)C
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 46 %

Procedure:
A solution of 12.3g (0.11 mole) of potassium tert-butoxide in 100 ml of dimethyl sulfoxide (under a nitrogen atmosphere) is cooled in a cold water bath and treated dropwise with a solution of 16.6 g (0.075 mole) of 3-hydroxy-5-methoxy-2-benzofuran carboxylic acid, methyl ester. The mixture is stirred for 45 minutes after completion of the addition, and 7.0 ml (9.2 g; 0.075 mole) of 2-bromopropane is added in one portion. After stirring for 24 hours at room temperature, the reaction mixture is added to 1.5 kg of ice/water and stirred an additional hour. The precipitated product is filtered and washed with water. The crude yield is 9.0 g (46% yield). A sample recrystallized from aqueous methanol yields analytically pure 5-methoxy-3-(1-methylethoxy)-2-benzofurancarboxylic acid methyl ester, mp 66°-68° C.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:34][CH2:33]1.CN1CCCC1>O1CCOCC1.CC#N.O>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH:38]2[CH2:43][CH2:42][N:41]([C:24]([NH:23][C:19]3[CH:18]=[C:17]([O:16][C:13]4[CH:14]=[N:15][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[O:30])=[CH:11][CH:12]=4)[CH:22]=[CH:21][N:20]=3)=[O:29])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)C(C)(C)C)nc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of Example C2 (0.120 g, 0.29 mmol), 1-methyl-4-(piperidin-4-yl)piperazine (0.053 g, 0.290 mmol) and N-methylpyrrolidine (0.012 g, 0.15 mmol) in dioxane (5 mL) was heated at 80° C. for 2 days. The reaction mixture was concentrated to dryness. The residue was dissolved in DCM and stirred with sat'd NaHCO3. The aqueous layer was back-extracted with DCM (3×) and the organic phases combined, dried (Na2SO4) and concentrated to afford a light brown oil. The crude residue was purified via silica gel chromatography (MeOH/DCM/Et3N) to afford a light yellow oil, which was dissolved in MeCN/H2O, frozen and lypholized overnight to afford 4-(4-methylpiperazin-1-yl)-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperidine-1-carboxamide as a white solid (63 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.22 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.12-8.05 (m, 2H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H), 4.13-4.02 (m, 2H), 3.38-3.31 (m, 1H), 2.77-2.64 (m, 2H), 2.52-2.26 (m, 8H), 2.16 (s, 3H), 1.75-1.62 (m, 2H), 1.31-1.23 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z: 539.4 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-])=O.CO.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:19][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1ccc(OCCOCc2ccccc2)cc1N

Procedure:
1.6 G. of 2-amino-4-(2-benzyloxyethoxy)-1-nitrobenzene is treated in 100 ml. of methanol and 50 ml. of water with 10 g. of sodium hydrosulfite (Na2S2O4) on the steam bath for 15 minutes. The reaction mixture is concentrated under vacuum and extracted with chloroform. Evaporationn of the extract affords 1,2-diamino-4-(2-benzyloxyethoxy)benzene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)/[CH:5]=[CH:6]/[C:7]1[NH:15][C:14]2[C:13](=[O:16])[N:12]([CH2:17][CH3:18])[C:11](=[O:19])[N:10]([CH2:20][CH3:21])[C:9]=2[N:8]=1.[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:25])[C:14]2[C:13](=[O:16])[N:12]([CH2:17][CH3:18])[C:11](=[O:19])[N:10]([CH2:20][CH3:21])[C:9]=2[N:8]=1
Reactant: O=C([O-])[O-]
Reactant: CCn1c(=O)c2[nH]c(/C=C/c3cccc(Br)c3)nc2n(CC)c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCn1c(=O)c2c(nc(/C=C/c3cccc(Br)c3)n2C)n(CC)c1=O
Temperature: 50 °C
Reaction time: 1.17 h

Procedure:
Compound g (2.5 g, 6.43 mmol) obtained in Reference Example 7 was dissolved in 20 ml of dimethylformamide. To the solution were added 2.22 g (16.1 mmol) of potassium carbonate and subsequently 0.8 ml (12.9 mmol) of methyl iodide, and the resulting mixture was stirred at 50° C. for 70 minutes. After cooling, insoluble matters were filtered off and water was added to the filtrate. The mixture was extracted three times with chloroform. The extract was washed three times with water and subsequently twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. Evaporation under reduced pressure gave 2.37 g (yield 92%) of crude Compound h as a yellow solid, which was further recrystallized from cyctohexane/toluene to give Compound h as a yellow powder.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([OH:10])[CH:4]=1.[CH3:11][N:12]1[C:16](S(C)(=O)=O)=[N:15][C:14]([C:21]([F:24])([F:23])[F:22])=[N:13]1>CS(C)=O>[CH3:11][N:12]1[C:16]([O:10][C:5]2[CH:6]=[CH:7][C:8]([NH2:9])=[CH:3][CH:4]=2)=[N:15][C:14]([C:21]([F:24])([F:23])[F:22])=[N:13]1
Reactant: Cn1nc(C(F)(F)F)nc1S(C)(=O)=O
Reactant: Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cn1nc(C(F)(F)F)nc1Oc1ccc(N)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
8 g of pulverised KOH are added to 10.9 g of p-aminophenol in 120 ml of dimethyl sulfoxide, and the mixture is stirred for 1/2 hour. Then 22.9 g of 1-methyl-3-trifluoromethyl-5-methylsulfonyl-1H-1,2,4-triazole are added, the reaction mixture is stirred for a further 2 hours and subsequently poured into 1 liter of ice water. The precipitated product is isolated by filtration, washed with water and dried. Yield: 19.6 g (76% of theory). Melting point: 111°14 112° C.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH:8]([CH3:10])[O:7][CH:6]([CH3:11])[CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:32]>>[Cl:32][CH2:2][CH2:3][N:4]1[CH2:9][CH:8]([CH3:10])[O:7][CH:6]([CH3:11])[CH2:5]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC1CN(CCO)CC(C)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1CN(CCCl)CC(C)O1
Temperature: 0 °C
Yield: 43 %

Procedure:
To a flask was added 5.0 g. (0.03 mole) of 4-(2-hydroxyethyl)-2,6-dimethylmorpholine in 50 ml. of carbon tetrachloride followed by 10.2 g. (0.04 mole) of triphenylphosphine. The mixture was stirred at reflux for three hours, then the reaction was cooled to 0° C., the triphenylphosphine oxide was filtered and the solvent stripped. The residue was dissolved in 10% aqueous hydrochloric acid and the by-products were extracted into ethyl acetate. The acid layer was then basified with ammonium hydroxide and extracted into ethyl acetate. The ethyl acetate solution was dried with magnesium sulfate, filtered, and concentrated. The crude product was further purified by flash chromatography to give 2.31 g. (43% yield) of 4-(2-chloroethyl)-2,6-dimethylmorpholine as a colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C.[F:52][C:53]([F:63])([F:62])C1C=CC=CC=1CBr>>[CH3:22][C:18]([CH3:23])([CH2:17][S:16][C:13]1[S:12][C:11]([NH:10][C:9]([N:8]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]=2[C:53]([F:63])([F:62])[F:52])=[O:24])=[N:15][CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2C(F)(F)F)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-Chloro-benzyloxy)-ethyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester and 2-trifluoromethylbenzyl bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]=[C:11]([O:15][CH3:16])[NH:10][C:9]2=[O:17])=[CH:4][CH:3]=1.[NH3:18]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:17])[N:10]=[C:11]([O:15][CH3:16])[NH:12][C:13]2=[O:14])=[CH:6][CH:7]=1.[NH4+:18]
Reactant: N
Agent: COc1nc(=O)n(-c2ccc(Cl)cc2)c(=O)[nH]1
Solvent: CO
Product: [NH4+]
Reaction time: 0.5 h

Procedure:
To a mixture of 10 parts of 3-(4-chlorophenyl)-6-methoxy-s-triazine-2,4(1H,3H)-dione and 100 parts of methanol is added one part of ammonia gas at 20° C. The solution is stirred for 30 minutes and then evaporated under vacuum to give 10.6 parts of ammonium 3-(4-chlorophenyl)-6-methoxy-s-triazine-2,4(1H,3H)-dione.
Reaction SMILES: [CH:1]([CH:4]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH:7]([CH:16]([CH3:18])[CH3:17])[N:6]=[N:5]1)([CH3:3])[CH3:2].[H][H]>C(O)(C)(C)C.[Rh]>[NH2:5][CH:4]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([NH2:6])[CH:16]([CH3:18])[CH3:17])[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(C)(C)O
Product: CC(C)C(N)CCCCCCCCC(N)C(C)C
Yield: 92.8 %

Procedure:
250 g (1 mole) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomer mixture) are dissolved in 1000 ml of tert -butanol in an agitator autoclave. After addition of 25 g of a rhodium/alumina catalyst (5% by weight of rhodium), hydrogen is introduced up to a pressure of 130 to 150 bar, whereupon hydrogenation is effected at 150° to 180° C. until the hydrogen uptake is complete. After cooling, excess hydrogen is blown off, the suspension is removed from the autoclave by suction and the catalyst is filtered off with suction over a small amount of hyflo (filter aid). The filtrate is concentrated by rotary evaporation and the product is purified by distillation, affording as main fraction 238 g (92% of theory) of 3,12-diamino-2,13-dimethyltetradecane as a colourless oil [b.p. 106°-109° C./0.01 torr; nD20 =1.4600; IR spectrum (in liquid) includes bands at 3355, 3278, 1613 cm-1 ].
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([O:9][CH2:10][C:11]([O:13]CC)=[O:12])[N:6]([CH3:16])[N:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:33]1=[O:34])[CH:29]([CH3:31])[CH3:30]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:1]([C:4]3[CH:8]=[C:7]([O:9][CH2:10][C:11]([OH:13])=[O:12])[N:6]([CH3:16])[N:5]=3)=[N:40][C:39]=2[N:32]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:33]1=[O:34])[CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(CC(C)C)c1=O
Reactant: CCOC(=O)COc1cc(C(=O)O)nn1C
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CC(C)Cn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)n(C)n3)nc2n(CC(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (3-carboxy-1-methylpyrazol-5-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[3-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-5-yloxy]acetic acid.