Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:30]=[CH:29][C:10]([C:11]([N:13]([CH3:28])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH:22]([NH:25][CH3:26])[C:21]4=[O:27])=[CH:16][CH:15]=3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>N1C=CC=CC=1>[C:31]([CH2:26][NH:25][CH:22]1[CH2:23][CH2:24][N:20]([C:17]2[CH:18]=[CH:19][C:14]([N:13]([CH3:28])[C:11](=[O:12])[C:10]3[CH:29]=[CH:30][C:7]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)=[CH:8][CH:9]=3)=[CH:15][CH:16]=2)[C:21]1=[O:27])(=[O:33])[CH3:32]
Reactant: CNC1CCN(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)CNC1CCN(c2ccc(N(C)C(=O)c3ccc(C4CCCCC4)cc3)cc2)C1=O

Procedure:
4-Cyclohexyl-N-methyl-N-[4-(3-methylamino-2-oxopyrrolidin-1-yl)phenyl]benzamide (52 mg) was mixed with pyridine (0.5 ml) and acetic anhydride (130 mg) and, after 3 hours, volatile fractions were removed in vacuo. This resulted in the product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[CH:4][CH:3]=1.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[C:42]1([CH2:48][C:49]([N:51]=[C:52]=[S:53])=[O:50])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])O.[Na+]>C(O)C.CCCCCC.C(OCC)C>[CH3:23][N:15]([CH:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)[C:14]([NH:13][C:9]1[CH:8]=[C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([NH:1][C:52]([NH:51][C:49](=[O:50])[CH2:48][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[S:53])=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1)=[O:24]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Reactant: O=C(Cc1ccccc1)N=C=S
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCO
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Yield: 2.2 %

Procedure:
3-[4-(4-Aminophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (60 mg) was dissolved in ethanol (1 ml) while stirring, and then D-10-camphorsulfonic acid (39.3 mg) was added thereto under a nitrogen atmosphere, followed by stirring for 5 min. Phenylacetyl isothiocyanate (toluene solution, 1.82 M, 0.074 ml) was added thereto, followed by stirring further for 1.5 hrs. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:5, then ethyl acetate). Fractions containing the crude product were concentrated to give a residue, which was then purified by LC-MS. The fractions containing the target compound were concentrated to give a residue, to which a saturated aqueous solution of sodium hydrogencarbonate was added to extract with ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:ethanol=9:1). Fractions containing the target compound were concentrated to give a residue, to which diethyl ether (0.3 ml)-hexane (0.1 ml) was then added to suspend. The solid was filtered off and dried under aeration to provide the titled compound (2.0 mg, 2.2%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[C:4]([Cl:11])[CH:3]=1.[NH3:12].[BH4-].[Na+].O>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:12])[CH3:9])=[C:4]([Cl:11])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1Cl
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: CC(N)c1ccc(Br)cc1Cl
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-(4-bromo-2-chlorophenyl)ethanone (2.430 g, 10 mmol), ammonia, 2.0 m solution in methanol (26 ml, 52 mmol) and titanium (iv) isopropoxide (6 ml, 21 mmol) was stirred for 16 h in a sealed vessel. Reaction then added to a freshly made suspension of sodium borohydride powder, 98% (4 g, 104 mmol) in MeOH (20 mL). Exothermic reaction started at 9:45 am, then continued to stir with a 45° C. external heating bath for 45 min. Water (10 mL) then added to reaction and stirred for an additional 10 min. Resulting white solid removed via filtration through Celite, and filtrated reduced in volume under reduced pressure. This suspension then partioned between 9:1 CHCl3/IPA (30 mL) and 1M NaOH (10 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). Combined organics dried over MgSO4, concentrated, then purified on silica (80 g) eluting with 0>5% 2M NH3 in MeOH/DCM. MS (ESI pos. ion) m/z: 234/236 (MH+). Calc'd exact mass for C8H9BrClN: 233/235. 1-(4-bromo-2-chlorophenyl)ethanamine isolated as a colorless oil.
Reaction SMILES: Cl[C:2]1([S:20]([CH2:22][CH3:23])=[O:21])[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[CH:3]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].N12CCCCC1C=NCCC2>C(OC(=O)C)C>[CH2:22]([S:20]([C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:21])[CH3:23]
Reactant: CCS(=O)C1(Cl)CC2CC(=O)N2C1C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Product: CCS(=O)C1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A suspension of benzyl 3-chloro-3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (54) (0.020 g) in ethylacetate (2 ml) was stirred at room temperature under argon and treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.009 g). After a period of 15 minutes the reaction mixture was washed with brine and dried over sodium sulphate. It was concentrated to give a single diastereoisomer of benzyl 3-ethylsulphinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (55) (0.017 g) as a gum; νmax (CHCl3) 2980, 1795 and 1730 cm-1 ; τ(d6 -acetone) 2.5-2.8 (5H, m, phenyl), 4.78 (2H, s, benzyl CH2), 5.71 (1H, tdd J9,5 and 3 Hz, C5-H), 6.49 (1H, dd J17 and 5Hz, C6-H), 6.82 (2H, d J 9 Hz, C4-H2), 6.84 (1H, dd J17 and 3 Hz, C6-H), 7.13 and 7.15 (2H, 2q J71/2Hz, SCH2) and 8.80 (3H, t J71/2 Hz, CH3).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[NH:7][C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[N:19]=[C:20]([CH2:23][CH2:24][CH3:25])[NH:21][CH:22]=1>O1CCOCC1>[CH3:17][C:18]1[N:19]=[C:20]([CH2:23][CH2:24][CH3:25])[N:21]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[NH:7][C:8](=[O:10])[CH3:9])[CH:22]=1
Reactant: CC(=O)Nc1ncsc1Br
Reactant: CCCc1nc(C)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCc1nc(C)cn1-c1scnc1NC(C)=O
Temperature: 100 °C
Yield: 0.8 %

Procedure:
N-(5-bromothiazol-4-yl)acetamide from example 2.4 (0.27 g, 1.22 mmol), potassium carbonate (0.17 g, 1.221 mmol) and 4-methyl-2-propyl-1H-imidazole from example 1.6 (0.15 g, 1.22 mmol) were added sequentially to dioxane (30 mL). The mixture was heated to 100° C. for 18 h. It was purified by pre-HPLC to give the title compound (3 mg, 0.01 mmol, 10%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[CH:7]=[O:8])[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH3:18])[CH2:7][OH:8])[CH3:2]
Reactant: CCCOCCOc1ccc(C=O)cc1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOCCOc1ccc(CO)cc1OCC
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Into a solution of 3-ethoxy-4-(2-propoxyethoxy)benzaldehyde (7.34 g) in methanol (30 ml) was added at 0° C. sodium borohydride (1.10 g), and the resulting mixture was stirred for one hour. After concentration under reduced pressure, 1 N hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was concentrated under reduced pressure to obtain 3-ethoxy-4-(2-propoxyethoxy)benzyl alcohol (7.35 g) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH3:31]OC(OC)N(C)C>>[Cl:19][C:6]1[CH:5]=[C:4]([N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:31])[N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Reactant: COC(OC)N(C)C
Product: CC(C)c1cc(Oc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Temperature: 25 °C
Yield: 73 %

Procedure:
A suspension of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]isoindole-1,3-dione (65) (84.5 g, 190.2 mmol) in N,N-dimethylformamide dimethyl acetal (250 mL) was heated to reflux for 5 h. At this time, the reaction was cooled to room temperature. The solids that resulted were collected by filtration, washed with a 1:1 mixture of methyl tert-butyl ether:heptane (70 mL) followed by heptane (70 mL) and dried under vacuum to afford 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-isoindole-1,3-dione (66) (63.57 g, 73%) as an off-white solid; ES(+)-LRMS for C22H17Cl2N3O4 (M+H)+ at m/z=458. Exact Mass=457.0596; Molecular Weight=458.30.
Reaction SMILES: [N+](C1C=CC(COC([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]3[N:21]=[C:22]([N:25]4[CH2:28][CH:27]([S:29][C:30]5[C@H:31]([CH3:54])[C@@H:32]6[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]6[C:34]=5[C:35]([O:37]CC5C=CC([N+]([O-])=O)=CC=5)=[O:36])[CH2:26]4)[O:23][CH:24]=3)=[O:19])[CH2:13]2)=O)=CC=1)([O-])=O>O1CCCC1>[NH:12]1[CH2:16][CH2:15][C@@H:14]([NH:17][C:18]([C:20]2[N:21]=[C:22]([N:25]3[CH2:28][CH:27]([S:29][C:30]4[C@H:31]([CH3:54])[C@@H:32]5[C@@H:49]([C@H:50]([OH:52])[CH3:51])[C:48](=[O:53])[N:33]5[C:34]=4[C:35]([OH:37])=[O:36])[CH2:26]3)[O:23][CH:24]=2)=[O:19])[CH2:13]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N[C@@H]5CCN(C(=O)OCc6ccc([N+](=O)[O-])cc6)C5)co4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)N[C@@H]5CCNC5)co4)C3)[C@H](C)[C@H]12
Reaction time: 4 h
Yield: 45.6 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-{1-[4-((3R)-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-3-ylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (320 mg, 0.404 mmol) (obtained as described in Example 81(1)) in a mixture of tetrahydrofuran (16 ml) and distilled water (16 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal (320 mg) at room temperature for 4 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate and distilled water. The resulting mixture was shaken in a separatory funnel and the aqueous layer was separated and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→distilled water:acetonitrile (79:21)) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-{1-[4-((3R)-pyrrolidin-3-ylcarbamoyl)-1,3-oxazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (88 mg, yield 46%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH:3]([C:5]1[S:9][C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH3:20])[OH:4].Br[CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=1.[H-].[Na+].O>CN(C)C=O>[F:33][C:27]1[CH:26]=[C:25]([CH2:24][O:4][CH:3]([C:5]2[S:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=3)=[N:7][C:6]=2[CH3:20])[C:2]([F:1])([F:21])[F:22])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(F)(F)F
Reactant: N#Cc1ccc(CBr)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(OCc1ccc(C#N)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
1.30 g 2,2,2-Trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol and 815 mg 4-Bromomethyl-2-fluoro-benzonitrile were dissolved in 40 ml dimethylformamide. 192 mg sodium hydride were added and the mixture stirred at room temperature for one hour. Then 15 ml water were added and the mixture extracted three times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by reversed phase HPLC to obtain 840 mg 2-Fluoro-4-{2,2,2-trifluoro-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxymethyl}-benzonitrile as an oil.
Reaction SMILES: [OH:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25].[OH-].[Na+].[Na+].[I-].Cl[CH2:31][C@@H:32]([OH:35])[CH2:33][OH:34]>C(O)(C)C.C(O)=O>[OH:35][C@@H:32]([CH2:33][OH:34])[CH2:31][O:1][C:2]1[C:23]([CH3:24])=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:17][C:16]([CH3:18])=[C:15]3[C:11]=2[CH2:12][C@H:13]2[C:19]([CH3:21])([CH3:20])[C@H:14]23)=[O:9])=[CH:4][C:3]=1[CH3:25]
Reactant: OC[C@H](O)CCl
Reactant: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CC(C)O
Product: Cc1cc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OC[C@@H](O)CO
Temperature: 90 °C
Reaction time: 8 h
Yield: 34.5 %

Procedure:
To a solution of (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-hydroxy-3,5-dimethyl-benzylamide (8.9 mg, 0.025 mmol) in isopropanol (1 mL) is added 2 N aq. NaOH (100 μL), NaI (1 mg, 0.007 mmol) and (S)-3-chloro-propane-1,2-diol (11.1 mg, 0.1 mmol). The reaction mixture is heated to 90° C. and shaken for 8 h before it is cooled to rt. Formic acid (0.2 mL) is added and the reaction mixture is separated by prep. HPLC to give (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 4-((S)-2,3-dihydroxy-propoxy)-3,5-dimethyl-benzylamide (3.7 mg) as a colourless lyophilisate. LC-MS: tR=0.94 min, [M+1]+=430.27.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[CH:9][C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[N:15]([CH2:23][O:24][CH3:25])[C:14]=2[CH:26]=1>N1C=CC=CC=1>[N:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:9]=1[C:10]1[CH:11]=[CH:12][C:13]2[S:18][C:17]3[N:19]=[CH:20][CH:21]=[N:22][C:16]=3[N:15]([CH2:23][O:24][CH3:25])[C:14]=2[CH:26]=1
Reactant: COCN1c2cc(C=Nc3ccccc3N)ccc2Sc2nccnc21
Solvent: c1ccncc1
Product: COCN1c2cc(-c3nc4ccccc4[nH]3)ccc2Sc2nccnc21
Yield: 51.1 %

Procedure:
610 mg of 2-amino-1-[N-[(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)methylene]]aminobenzene was heated under reflux in 3 ml of pyridine for 8 hours. Then the reaction mixture was brought back to room temperature and eluted with ethyl acetate. The crystals thus precipitated were ground and filtered to thereby give 310 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][O:20][CH3:21])[C:9]([O:11][CH2:12][CH3:13])=[O:10].S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28].[Cl-].[Na+]>C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][C:16]1[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:14]([N+:27]([O-:29])=[O:28])[CH:15]=1
Reactant: CCOC(=O)c1ccc(OCCOC)c(OCCOC)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 20 L-volume glass reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, the acetic acid solution containing 2,023 g (6.78 moles) of ethyl 3,4-bis(2-methoxyethoxy)benzoate prepared in the Synthesis Example 1 was placed. To the solution, 318 g (3.18 moles) of concentrated sulfuric acid was gently added while stirring the solution at room temperature. The mixture was heated to 60 to 70° C. To the mixture, 1,857 g (20.34 moles) of 69 wt. % nitric acid was gently added while stirring the mixture. The resulting mixture was allowed to react for 2 hours while maintaining the temperature. After the reaction was complete, the reaction solution was cooled to room temperature. To the reaction solution, 5,200 mL of a 20 wt. % aqueous sodium chloride solution and 5,200 mL of toluene were added. The separated organic layer (toluene layer) was washed twice with 7,800 mL of a 1 mole per L aqueous sodium hydroxide solution, and further washed twice with 7,800 mL of a 20 wt. % aqueous sodium chloride solution. The organic layer was concentrated under reduced pressure to obtain 2,328 g of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate as an orange liquid (isolation yield: 100%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([O:19][CH2:20][S:21][CH3:22])=[CH:17][C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1>[Cl-].C(Cl)Cl>[Cl:12][C:13]1[C:18]([O:19][CH2:20][S:21]([CH3:22])=[O:9])=[CH:17][C:16]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:25]([CH3:34])[C:24]2=[O:35])=[C:15]([F:36])[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCS(C)=O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 1.0 g of 3-chloro-perbenzoic acid in 15 ml of metyylene chloride is added dropwise while stirring at 0° C. during 1 hour to a solution of 2.3 g of 1-[4-chloro-2-fluoro-5 -(methylthio)methoxy-phenyl]-3-methyl-4-trifluoromethyl-2,6-(1H,3H)-pyrimidinedione in 30 ml of methylene chloride. The reaction mixture is subsequently stirred at room temperature for 15 hours, washed with dilute aqueous sodium bicarbonate solution and then with water and dried over anhydrous sodium sulphate. The organic phase is evaporated to dryness under reduced pressure and the residue is purified by chromatography on a silica gel column using diethyl ether/ethyl acetate and thereafter ethyl acetate alone as the eluent. There is obtained 1-[4-chloro-2-fluoro-5-(methylsulphinyl) methoxy-phenyl]-3-methyl-4-trifluoromethyl-2,6(1H,3H)pyrimidinedione, 1H-NMR (CDCl3, 400 MHz): 7.33 ppm (d.1H). 7.27 ppm (2d,1H), 6.34 ppm (2s,1H). 4.91-5.05 ppm (m,2H), 3.54 ppm (d,3H), 2.72 ppm (s,3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)[CH2:8][CH2:7]1.[C@@H:22]12[C:31](=O)[O:30][C:28](=[O:29])[C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27]2.[ClH:33]>N1C=CC=CC=1.C(O)C>[ClH:33].[F:21][C:19]1[CH:18]=[CH:17][C:16]2[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]4[C:28](=[O:29])[CH:23]5[CH:22]([CH2:27][CH2:26][CH2:25][CH2:24]5)[C:31]4=[O:30])[CH2:7][CH2:8]3)=[N:13][O:14][C:15]=2[CH:20]=1
Reactant: NCCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1C2CCCCC2C(=O)N1CCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-(4-aminobutyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (4.7 g, 16.1 mmol) and cis-1,2-cyclohexanedicarboxylic anhydride (3.23 g, 21 mmol) in pyridine (45 ml) was heated at reflux for 8 hours. At the end of the reaction, pyridine was removed to dryness. The crude product was purified on a silica gel column. The material thus obtained weighed 3.18 g (45%) as a clear oil. This oil was dissolved in ethanol (15 ml), then was treated with HCl in ethanol (45 ml). Crystallization took place upon cooling. The crystals were collected, 3.2 g, m.p.=229-231° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])[CH:13]=[CH:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccsc1
Product: CN(C)C=CC(=O)c1ccsc1
Yield: 87 %

Procedure:
A mixture of 48.4 g of 3-acetylthiophene and 75 ml of dimethylformamide dimethyl acetal, under nitrogen, is heated for 15 hours on a steam bath. The reaction is concentrated in vacuo and the residue crystallized from methylene chloride/hexane to give 60.55 g (87%) of the desired product, mp 89°-90° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl.N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=2)(=[O:15])=[O:14])[CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O[C@@H]1CCOC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (R)-tetrahydrofuran-3-ol (25.4 g) in dichloromethane (250 mL) and pyridine (60 mL) is added at 0° C. N,N-dimethylaminopyridine (DMAP; 1 g) and p-toluene-sulfonylchloride (73 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCl solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0→95:5) to give the title compound. Yield: 59.5 g; Mass spectrum (ESI+): m/z=243 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](O)=[O:12])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2].[NH3:34].C(OCC)(=O)C>C(#N)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:12])[NH2:34])=[CH:7][C:6]=1[NH:14][C:15](=[O:33])[CH2:16][CH:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(SC)cc1OC
Reactant: N
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(SC)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
510 mg (3.15 mmol) of N,N'-carbonyldiimidazole were added to a solution of 1.142 g (2.42 mmol) of N-(2-t-butyl-5-carboxyphenyl)-3-(2-methoxy-4-methylthiophenyl)octanamide (prepared as described in Preparation 31A) in 10 ml of acetonitrile, and the resulting mixture was stirred at room temperature for 1 hour, after which 0.79 ml (12.1 mmol) of 28% w/w aqueous ammonia. The reaction mixture was stirred for 5 hours, after which it was diluted with water, and the diluted aqueous mixture was freed from the organic solvent by distillation under reduced pressure. The aqueous concentrate was extracted with ethyl acetate. The extract was washed with 2 N aqueous hydrochloric acid, with a 0.5 N aqueous solution of sodium hydroxide, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from ethyl acetate, to give 962 mg (yield 84%) of the title compound as crystals, melting at 171-172° C. (from ethyl acetate).