Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH:13]=1)[C:6]([O:8]C)=O.[NH3:31]>C(O)CO>[CH3:15][N:14]([C:12]1[CH:13]=[C:4]2[C:3](=[O:2])[NH:31][C:6](=[O:8])[C:5]2=[CH:10][C:11]=1[N:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(N(C)c2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: CN(c1ccccc1)c1cc2c(cc1N(C)c1ccccc1)C(=O)NC2=O

Procedure:
Analogously to Example 1, 66 mg (0.16 mmol) of 4,5-bis(N-methyl-N-phenylamino)phthalic acid dimethyl ester (Example 14 A)in 5 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled, and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed onsilica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the rifle compound in the form of slightly yellow crystals, FAB-MS: 358 [M+ +H], 1H-NMR (CDCl3): 3.05 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([O:65][C:66]([C@@H:68]1[CH2:72][CH2:71][CH2:70][NH:69]1)=[O:67])[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][C@H:68]1[C:66]([O:65][CH2:63][CH3:64])=[O:67])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-(ethoxycarbonyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[N:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:28]3[CH2:29][CH2:30][CH:25]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:26][CH2:27]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CCN(C2CCNCC2)CC1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCCCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 and 4-piperidinopiperidine were reacted using General Procedure B-3 to give 1′-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1,4′]bipiperidinyl, which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine in General Procedure A. Purification on silica yielded 107. NMR (CDCl3): 1.46 (m, 2H, CH2), 1.61-1.68 (m, 6H, 6×CH), 1.82-1.85 (m, 2H, 2×CH), 2.09-2.14 (m, 2H, CH2), 2.30 (m, H, CH), 2.54 (m, 4H, 4×CH), 3.04-3.07 (m, 2H, 2×CH), 3.81 (s, 2H, CH2), 3.89-3.91 (m, 4H, 2×CH2), 4.04-4.06 (m, 4H, 2×CH2), 4.64 (sbr, 2H, NH2), 6.58 (d, H, ArH, J=8.59 Hz), 7.26 (s, H, ArH), 8.47 (dd, H, ArH, J=8.58 Hz, 2.25 Hz), 9.16 (d, H, ArH, J=1.86 Hz). MS: (ESI+): MH+=494.32
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[F:12][C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15](I)([F:20])[C:16]([F:19])([F:18])[F:17]>>[F:17][C:16]([F:18])([F:19])[C:15]([F:20])([C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:9]=1)[C:14]([F:22])([F:23])[C:13]([F:25])([F:24])[F:12]
Reactant: FC(F)(F)C(F)(F)C(F)(I)C(F)(F)F
Reactant: Nc1ccccc1C(F)(F)F
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1C(F)(F)F

Procedure:
According to the method of 1-1 of Example 1, a target compound was prepared from 2-(trifluoromethyl)aniline and nonafluoro-s-butyliodide under the light-shielding reaction condition.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCOCC.O>[CH2:17]([N:12]1[CH:11]=[C:10]([C:13]([F:14])([F:16])[F:15])[N:9]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: FC(F)(F)c1cnc(-c2ccc(Br)cc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: FC(F)(F)c1cn(Cc2ccccc2)c(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2-(4-bromophenyl)-5-(trifluoromethyl)-1H-imidazole (3 g), benzyl bromide (3.52 g), potassium carbonate (2.85 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature overnight. To the reaction mixture were added water and ether, and the liquids were separated. The organic layer was separated, washed with water and then with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene, and purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 70:30) to obtain 1-benzyl-2-(4-bromophenyl)-4-(trifluoromethyl)-1H-imidazole (3.40 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3([C:23]([O:25]CC4C=CC=CC=4)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.C(O)(=O)C>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(NC2CCN(CCC3(C(=O)OCc4ccccc4)CCCCC3)CC2)nc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(NC2CCN(CCC3(C(=O)O)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a solution of benzyl 1-[2-[4-(5-methylpiridin-2-yl-amino)piperidin-1-yl]ethyl]cyclohexanecarboxylate (160 mg, 0.37 mmol) in ethanol (16 mL) was added 10% palladium carbon (80 mg) at room temperature. The mixture was stirred at room temperature under hydrogen atmosphere for 24 hours. Acetic acid was added to the mixture, and it was filtered with Celite and concentrated under reduced pressure. Methanol and diethyl ether were added to the residue, and the solution was stirred under ice cooling for 1 hour. The crystals were recovered by filtration to give the title compound (100 mg).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:15][CH2:14][NH:13][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCCN1CCCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)NCCN1CCCC1

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-(2-aminoethyl)pyrrolidine as starting materials to give the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([NH:22][CH2:23][C@@H:24](O)[CH3:25])(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[NH2:22][CH2:23][C@@H:24]([N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1)[CH3:25]
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Reactant: C[C@H](O)CNC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (0.91 g, 3.80 mmol) was reacted with N-Boc-(S)-1-amino-2-propanol (1.00 g, 5.71 mmol) in the presence of triphenylphosphine and DIAD using the method of Example 99. After Boc-deprotection 0.30 g (30%) of the title compound was obtained. 1H-NMR (400 MHz; d6-DMSO): δ 1.43 (d, 3H), 2.91-3.40 (m, 1H), 4.29-4.39 (m, 1H), 4.71-4.85 (m, 1H), 7.97 (d, 1H), 7.89 (d, 1H), 7.96 (d, 1H), 7.97 (d, 1H), 8.11 (dd, 1H). m/z [260.7+1].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].N1CC[CH2:15][CH2:14][CH2:13]1.FC(F)(F)C(O)=O>CC(C)=O>[Br:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[O:11][C:14]([CH3:15])([CH3:13])[CH2:2][C:1]2=[O:3]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2cc(Br)ccc2O1

Procedure:
In another exemplary reaction sequence shown in Reaction Scheme 15, 4-bromophenol is reacted with acetyl chloride (AcCl) to provide the corresponding ester, and the ester made to undergo a Fries rearrangement under Friedel Crafts conditions to provide 2-acetyl-4-bromophenol. 2-Acetyl-4-bromophenol is reacted with acetone in the presence of piperidine and trifluoroacetic acid (TFA) to give 6-bromo-2,2-dimethyl-chroman-4-one. The latter compound is reacted with the Grignard reagent of the formula R1MgX and then with acid to provide the 6-bromo-2,2-dimethyl-chromene derivative of Formula 17.
Reaction SMILES: [CH3:1][C:2]([O:27]C1CCCCO1)([CH3:26])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4].C(O)(=O)C.C1COCC1>O>[OH:27][C:2]([CH3:26])([CH3:1])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)OC4CCCCO4)c3n2)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)O)c3n2)cc(OC)c1OC
Temperature: 50 °C

Procedure:
2-Methyl-2-(tetrahydro-pyran-2-yloxy)-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one, 0.012 gm, was mixed with 0.8 ml acetic acid, 0.4 ml THF and 0.2 ml water and heated for 90 minutes in a 50° C. oil bath. The mixture was concentrated, saturated aqueous sodium bicarbonate was added and the mixture extracted twice with ethyl acetate, dried over magnesium sulfate, filtered and stripped and the solid dried overnight at 2 torr in an 80° C. vacuum oven to give 2-Hydroxy-2-methyl-1-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one. (M+H)+=372.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>CC(C)=O.ClCCl>[C:21]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12])(=[O:23])[CH3:22]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.1 %

Procedure:
4-Hydroxy-3-nitro-benzoic acid (5.49 g, 30 mmol) was dissolved in acetone (10 ml), triethylamine (10 ml) and acetic acid anhydride (5.67 ml, 60 mmol). The solution was stirred for 24 h at rt. The reaction mixture was added dichloromethane (100 ml), ice (20 g) and acidified by addition of concentrated hydrochloric acid. The aqueous phase was extracted with dichloromethane (2×25 ml). The combined organic phases were stirred with sodium sulphate added activated carbon, filtered and evaporated. Recrystallisation from EtoAc:Heptane gave 3.45 g (51%) pure material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21].Cl.S(=O)(=O)(O)O>[Fe].C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[C:14]2[CH2:17][CH2:18][CH2:19][CH2:20][C:13]=2[C:12]1=[O:21]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc([N+](=O)[O-])ccc1F
Agent: [Fe]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1

Procedure:
The compound (VIII) is prepared by reacting the compound (VII), i.e. N-(2-fluoro-5-nitrophenyl)-3,4,5,6-tetrahydrophthalimide, with a 2 to 5 equivalent amount of iron powders (e.g. reduced iron, electrolytic iron) in a solvent in the presence of a catalytic amount of an acid (e.g. hydrochloric acid, sulfuric acid, acetic acid) at a temperature of 90° to 120° C. for a period of 1 to 10 hours.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]#[N:23])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[ClH:24]>CO.[Pd]>[ClH:24].[NH2:23][CH2:22][CH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=1
Reactant: N#CCc1ccccc1-c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCCc1ccccc1-c1cccc(O)c1
Reaction time: 48 h

Procedure:
A mixture of (3′-benzyloxybiphenyl-2-yl)acetonitrile from Step B (140 mg, 0.47 mmol), conc. HCl (0.060 mL, 0.73 mmol), and 10% Pd-C (30 mg) in MeOH (15 mL) was shaken under an atmosphere of hydrogen (ca. 50 atm) for 48 hours. The reaction mixture was filtered through a celite pad, washing with MeOH, and the filtrate was concentrated under reduced pressure to give the titled product, which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].C(N(CC)CC)C.[CH:22](=[O:26])[CH2:23][CH2:24][CH3:25]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:3][C@H:2]([C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CCCC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21
Yield: 80 %

Procedure:
A solution of N-propionyl-2-benzoxazolone (100.0 g) in anhydrous CH2Cl2 (1100 mL) was cooled to 3° C. with mechanical stirring under N2 atmosphere. TiCl4 (58.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting yellow slurry was stirred vigorously for 40 minutes, then triethylamine (87.4 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 10 minutes). The resulting deep red solution was stirred for 80 minutes. Butyraldehyde (58.9 mL) was added at a rate such that the internal temperature remained below 10° C. (ca. 20 minutes), and the reaction was followed by thin-layer chromatography (4:1 hexanes/ethyl acetate). After stirring for 90 minutes, the reaction was quenched by addition of 450 mL of 2 N HCl. The phases were separated, and the aqueous phase was extracted 3 times with 750-mL portions of ether. The organic phases were combined and washed three times with 200-mL portions of 2 N HCl. The acidic washes were combined and back-extracted 3 times with 150-mL portions of ether. The combined organic extract was washed once with 300 mL of sat. aq. NaHCO3, and once with 300 mL of sat. aq. NaCl. The organic phase was then dried over MgSO4, filtered, and concentrated under vacuum to a yellow slurry. The product was collected by vacuum filtration and rinsed with hexanes to yield a colorless solid. Concentration of the filtrate yielded a second crop of product, which was collected in the same manner, giving a combined 103 g (80% yield) of crystalline product; mp=123-4° C. The mother liquor can be chromatographed (4:1 hexanes/ethyl acetate) to yield additional product. 1H-NMR (CDCl3, 400 MHz): δ 8.10 (1H, m), 7.23-7.32 (3H, m), 4.12 (1H, m), 3.98 (1H, dq, J=3,7), 2.26 (1H, br s), 1.38-1.64 (4H, m), 1.34 (3H, d, J=7), 0.98 (3H, t, J=7). 13C-NMR (CDCl3, 100 MHz): δ 176.4, 151.1, 142.2, 127.8, 125.5, 124.9, 116.3, 109.9, 71.3, 43.7, 36.2, 19.2, 13.9, 10.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH2:16]1N2CN3CN(C2)CN1C3.C(OC(=O)C)(=O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:8](=[O:15])[CH:9]([CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:16]2
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C)CCC(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(C)(C)CC1Cc2cccc(Cl)c2C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 74 %

Procedure:
101.8 g (453 mmole) 1-(2-Chloro-phenyl)-4,4-dimethyl-pentan-1-one, 133.4 g (2.1 eq.) urotropine and 124.7 g (2.7 eq.) of acetic anhydride were placed in a 1000 ml roundbottom flask and the mixture was stirred at 80° C. for 4 h. Then 200 ml water and 200 ml 2M NaOH were added and the mixture was extracted two times with 250 ml dichloromethane each. The organic layer was washed two times with 150 ml saturated aqueous ammonium chloride and dried over magnesium sulphate. The solvent amount was reduced in vacuo to a total of 250 ml volume and the solution was added dropwise over a period of 2.5 h to 1000 g of hot (70-75° C.) concentrated sulphuric acid. After stirring for an additional 30 min at 75° C. the mixture was allowed to stand overnight at room temperature. The mixture was poured onto approx. 800 g of ice and extracted three times with 250 ml dichloromethane each. The organic layer was washed twice with 250 ml of a saturated sodium bicarbonate solution and once with 200 ml of a saturated sodium chloride solution. After drying over magnesium sulphate the solvent was removed in vacuo. The product was purified by column chromatography on silica (heptane/dichloromethane 1:1) to yield 79.4 g (74%) of the desired product as a slightly off-white oil, which slowly crystallized. 1H-NMR (400 MHz, CDCl3): δ=7.44 (t, 1H, aromatic), 7.30 (d, 1H, aromatic), 7.27 (d, 1H, aromatic), 3.38 (dd, 1H, COCH), 2.79, 2.60 (2×m, 2H, benzylic), 2.10, 1.21 (2×m, 1H, CH2-t-Bu), 0.90 (s, 9H, t-Bu) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]([CH2:7][C:8](N(C)C)=[O:9])[CH2:4][CH2:5][CH:6]=1.C([BH-](CC)CC)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:3]([CH2:7][CH2:8][OH:9])[CH2:4][CH2:5][CH:6]=1
Reactant: CN(C)C(=O)CC1CCC=C1Br
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CCC=C1Br
Yield: 58 %

Procedure:
2-(2-Bromo-cyclopent-2-enyl)-N,N-dimethyl-acetamide (Intermediate FOUR1) (1.93 g, 8.3 mmol) in THF (50 mL) was reacted with lithium triethylborohydride (19 mL, 1 M in THF) at 0° C. for 1 h. The mixture was treated with an aqueous work-up and the resultant alcohol was purified by column chromatography to give 0.92 g of 2-(2-bromo-cyclopent-2-enyl)-ethanol Intermediate FIVE1.
Reaction SMILES: Br[CH2:2][C@@H:3]([CH3:23])[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[S:6]1(=[O:22])=[O:21].FC1C=CC=C[C:26]=1[N:31]1C2C=CC=CC=2NS1(=O)=O.BrC[C@@H](C)CO>>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:5]([CH2:4][C@H:3]([CH3:23])[CH2:2][NH:31][CH3:26])[S:6]1(=[O:22])=[O:21]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Reactant: C[C@H](CBr)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O
Agent: C[C@@H](CO)CBr
Product: CNC[C@@H](C)CN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to Example 19, step 1, 1-[(2S)-3-bromo-2-methylpropyl]-3-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide was prepared from 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide and (S)-3-bromo-2-methylpropan-1-ol giving 0.26 g of the desired product.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH2:4][C:3](=O)[CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH2:29]>C1(C)C=CC=CC=1>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][NH:29][C:3]1[CH2:2][O:1][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=[O:12])[CH:4]=1
Reactant: CN(C)CCN
Reactant: O=C1COc2ccccc2C(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C)CCNC1=CC(=O)c2ccccc2OC1
Temperature: 25 °C

Procedure:
A solution of 88 g (0.5 mole) 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dione and a spatula tip of p-toluene sulfonic acid in 750 ml toluene are mixed while stirring with 44 g (0.5 mole) N,N-dimethylethylenediamine and subsequently stirred to the end of the reaction at room temperature. After concentration of the solution, a product is obtained by filtering off the solution under suction and subsequently recrystallizing from benzene/ligroin. 108 g (88% of the theoretical yield) of 3-(β-dimethylaminoethylamino)-1-benzoxepin-5(2H)-one are obtained. The melting point of this derivative is 100 to 101° C.
Reaction SMILES: C(O[C:9]([N:11]1[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:13]2([S:17][CH2:16][CH2:15][S:14]2)[CH2:12]1)=[O:10])C1C=CC=CC=1.S1C2(C[C@@H](C(OCC)=O)NC2)SCC1.[CH2:39]([O:46][C:47]([NH:49][CH2:50]C(O)=O)=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:46][C:47]([NH:49][CH2:50][C:9]([N:11]1[C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:13]2([S:14][CH2:15][CH2:16][S:17]2)[CH2:12]1)=[O:10])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2
Agent: CCOC(=O)[C@@H]1CC2(CN1)SCCS2
Product: CCOC(=O)[C@@H]1CC2(CN1C(=O)CNC(=O)OCc1ccccc1)SCCS2

Procedure:
Convert 2.22 g of 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester (prepared as described in paragraph A) to 1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester as described in Example 1 and couple this compound with 1.5 g of N-benzyloxycarbonylglycine, N-hydroxysuccinimide ester as described in Example 2 to yield 7-(N-benzyloxycarbonylglycyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(S)-carboxylic acid, ethyl ester, a yellow oil [α]D24 -15.9°. (ethanol).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O.[C:17]([O:21][C:22]([NH:24][C@H:25]([C:30]([OH:32])=O)[CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].ON1C(=O)CCC1=O.[N:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(OCC)(=O)C>[CH3:29][CH:27]([CH3:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[C:30]([N:50]1[CH2:51][CH2:52][N:47]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][N:41]=2)[CH2:48][CH2:49]1)=[O:32]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: c1ccc(N2CCNCC2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
Under cooling with ice, an ethyl acetate solution (40 ml) of N,N'-dicyclohexylcarbodiimide (10.3 g) was added dropwise to an ethyl acetate solution (150 ml) containing tert-butoxycarbonyl-L-leucine monohydrate (12.5 g) and N-hydroxy succinimide (5.76 g), and the mixture was stirred at room temperature for 3 hours. While cooling again with ice, 1-(2-pyridyl)piperazine (8.16 g) was added, and the mixture was stirred overnight at room temperature. The precipitate was removed by filtration, and the filtrate was washed first with an aqueous sodium carbonate solution and then with a saturated sodium chloride solution, dried over sodium sulfate and distilled under reduced pressure to remove the solvent, whereupon a crude reaction mixture was obtained. The reaction mixture was purified by silica gel column chromatography (developing solvent:methylene chloride:methanol=10:1) to yield 16.1 g of tert-butyl (s)-3-methyl-1-[4-(2-pyridyl)piperazine-1-yl carbonyl]butylcarbamate (yield: 85.6%).