Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([CH2:16][Br:17])[CH:15]=1)[O:5][Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:7])[CH3:8]
Reactant: Cc1cc(Br)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(CBr)c1

Procedure:
(3-Bromo-5-methyl-phenoxy)-tert-butyldimethylsilane (3.32 mmol) [prepared according to the procedure of J. E. Baldwin et al, Tetrahedron, 1991, 47(29), 5603], N-bromosuccinimide (3.65 mmol), and benzoyl peroxide (0.332 mmol) were dissolved in dichloromethane (10 mL) and the reaction mixture irradiated for 4 hours. Diluted with dichloromethane and washed with water, dried over magnesium sulfate and concentrated to dryness. The crude material was purified by column chromatography on silica gel with 10% ethyl acetate/cyclohexane to give (3-bromo-5-bromomethyl-phenoxy)-tert -butyldimethylsilane as a colorless oil. This material was subjected to the conditions described in the first part of EXAMPLE 1A, but using (3-bromo-5-bromomethyl-phenoxy)-tert-butyldimethylsilane in place of 3-bromobenzylbromide, to give 3-bromo-N,N-(bis-tert-butoxycarbonyl)-5-(tert-butyldimethylsilyloxy)benzylamine as a colorless oil. MS (EI) 516 and 518 (M++H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.[C:24](=[O:26])=[O:25]>C1CCCCC1>[SH:10][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[C:24]([OH:26])=[O:25]
Reactant: CC(C)c1ccccc1S
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: CC(C)c1cccc(C(=O)O)c1S
Reaction time: 24 h

Procedure:
To a solution of 1.0 mmol 2-isopropylthiophenol and 2.2 mmol TMEDA in 2 mL cyclohexane was added 2.2 mmol n-BuLi. Then after stirring 24 h it was added to solid CO2 and stirred for 16 h when extraction and chromatography provided 2-mercapto-3-isopropylbenzoic acid. The methyl ester of this was treated as in example 3 to provide the title compound.
Reaction SMILES: [C:1](=O)([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:2]CC1C=CC=CC=1.O.[NH2:20][NH2:21]>>[C:1]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:2])[NH:20][NH2:21]
Reactant: O=C(OCc1ccccc1)OCc1ccccc1
Reactant: NN
Solvent: O
Product: NNC(=O)OCc1ccccc1

Procedure:
The 2nd step is carried out analogously in further experiments B, C, and D at room temperature using the dibenzyl carbonate and hydrazine hydrate ratios given in Table 1. The amount and purity of benzyl carbazate that is obtained are likewise summarized in Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16]CC)=O)[C:8]([C:19]([O:21]CC)=O)=[C:7]2[OH:24])([O-:3])=[O:2].[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[OH:16][C:14]1[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[C:7](=[O:24])[C:8]=2[C:19](=[O:21])[N:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:32]=1
Reactant: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2c(O)c1C(=O)OCC
Reactant: NNc1ccccc1
Solvent: CCO
Product: O=c1c2cc([N+](=O)[O-])ccc2[nH]c2c(O)nn(-c3ccccc3)c(=O)c12
Temperature: 25 °C

Procedure:
To a stirred suspension of diethyl 6-nitro-4-hydroxy-quinoline-2,3-dicarboxylate (1.670 g, 5.00 mM) in ethanol (30 mL) was added phenylhydrazine (3.44 mL, 35.00 mM) to give a deep red solution. The solution was heated to reflux for 1 hour and concentrated to about 15 mL. Continued heating gave a thick suspension which was diluted with ethanol (5 mL) and refluxed for 16 additional hours. The mixture was cooled to room temperature and filtered to give the phenylhydrazine salt of the title compound as a tan solid. This material was refluxed in glacial acetic acid (25 mL) for 2 hours and cooled to room temperature. Filtration gave the title compound (1.01 g, 58%) as a tan powder, mp 368° C. (decomp.); MS(CI): 351 (M+H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@:5]12[O:12][C@@H:9]([CH2:10][CH2:11]1)[C:8](=[O:13])[CH2:7][C:6]2=[O:14])[CH3:2].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:31][C:32]1[CH:37]=[CH:36][C:35]([Pb+3])=[C:34]([CH2:39][CH3:40])[CH:33]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:31][C:32]1[CH:37]=[CH:36][C:35]([CH:7]2[C:8](=[O:13])[C@H:9]3[O:12][C@:5]([CH2:4][O:3][CH2:1][CH3:2])([CH2:11][CH2:10]3)[C:6]2=[O:14])=[C:34]([CH2:39][CH3:40])[CH:33]=1
Reactant: CCOC[C@]12CC[C@H](O1)C(=O)CC2=O
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC[C@]12CC[C@H](O1)C(=O)C(c1ccc(Br)cc1CC)C2=O
Temperature: 80 °C
Yield: 29.2 %

Procedure:
(1S*,5S*)-1-Ethoxymethyl-8-oxabicyclo[3.2.1]octane-2,4-dione (0.8 g, 4.04 mmol) and 4-dimethylaminopyridine (2.4 g, 19.67 mmol) are added to a mixture of chloroform (16 ml) and toluene (4 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2-ethylphenyllead triacetate (2.49 g, 4.38 mmol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×25 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1S*,5S*)-3-(4-bromo-2-ethylphenyl)-1-ethoxymethyl-8-oxabicyclo[3.2.1]octane-2,4-dione as white solid (0.45 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1C=CO[N:7]=1)=[O:4].[N:11]1[CH:16]=NC=[N:13][C:12]=1N>>[Br:1][CH2:2][C:3]([NH:5][C:6]1[N:7]=[CH:16][N:11]=[CH:12][N:13]=1)=[O:4]
Reactant: Nc1ncncn1
Reactant: O=C(CBr)Nc1ccon1
Product: O=C(CBr)Nc1ncncn1

Procedure:
This compound is prepared by an analogous method to 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) by replacing 3-aminoisoxazole with [1,3,5]triazin-2-ylamine.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][S:6][CH2:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O(C)[Na].CO>>[OH:16][CH:3]1[CH:4]=[CH:5][S:6][CH:7]1[C:8](=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)CCSCC(=O)c1ccccc1
Agent: CO[Na]
Solvent: CO
Product: O=C(c1ccccc1)C1SC=CC1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
23.8 parts of 3-(benzoylmethylthio)-propionic acid methyl ester are added in the course of 30 minutes to 36 parts of a 30 percent strength by weight NaOCH3 /MeOH solution which has been cooled to 0° C., and the mixture is stirred for 2 hours at from 0° to 10° C. The end product is isolated from the reaction mixture by the method described in Example 14(b). 18.5 parts (90% of theory) of 3-hydroxy-2-benzoyldihydrothiophene of boiling point 137°-140° C./0.16-0.08 mbar are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[S:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[Br:13].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)=O>CCO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10]2[S:12][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[Br:13]
Reactant: COC(=O)c1cc(C(N)=S)ccc1Br
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Temperature: 70 °C
Yield: 81.9 %

Procedure:
A mixture of 2-bromo-5-carbamothioylbenzoic acid methyl ester (which may be prepared as described for Intermediate 5; 13.7 g, 50 mmol) and 2-bromo-3′,4′-dichloroacetophenone (available from Aldrich Chemical Company, Inc.; 13.5 g, 50.5 mmol) in EtOH (200 mL) was heated at 70° C. overnight. The solid was filtered off to give 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (18.14 g, 82%).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=O)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2].[C:14]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)#[CH:15]>C(O)C.C(O)(=O)C>[C:1]([C:5]1[CH:12]=[CH:11][CH:10]=[C:7]([CH:8]=[N:20][C:19]2[CH:21]=[CH:22][C:16]([C:14]#[CH:15])=[CH:17][CH:18]=2)[C:6]=1[OH:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(C)(C)c1cccc(C=O)c1O
Solvent: CCO
Solvent: CC(=O)O
Product: C#Cc1ccc(N=Cc2cccc(C(C)(C)C)c2O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43 %

Procedure:
3-tert-butyl salicylaldehyde (1) (0.70 g/3.93 mmol) and 4-ethynyl aniline (0.49 g/4.2 mmol) were dissolved in 100 ml of ethanol. Molecular sieves (3 Å, 15 g) and a few drops of glacial acetic acid were added and the mixture was stirred at room temperature for three days. After filtration over sodium sulphate and removal of the solvent, the residue was extracted several times with n-pentane. The solution was filtered again over sodium sulphate, and the solvent was removed. The title compound was obtained as a yellow powder. Yield: 43%.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2Cl)=[O:11])[CH2:4][CH2:3]1.[C:25]1(B(O)O)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:2]4[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(NCC1CCC(F)(F)CC1)c1c(C2=CCCCC2)ccc2nc(C3=CCCCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide, cyclohexene-1-yl-boronic acid, cesium carbonate and tetrakis(triphenylphosphine)palladium (0). 1H NMR (400 MHz, DMSO-d6): δ 8.83 (t, J=5.9 Hz, 1H), 7.89-8.00 (m, 3H), 7.73-7.76 (m, 1H), 6.91 (s, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.65-2.66 (m, 2H), 2.31-2.32 (m, 2H), 1.86-2.01 (m, 2H), 1.74-1.76 (m, 3H), 1.65-1.67 (m, 6H), 1.27-1.30 (m, 2H). m/z: 419 [M+H]+
Reaction SMILES: Cl[CH2:2][CH:3]1[C:15](=[O:16])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:17])[C:6]=2[CH2:5][CH2:4]1.[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1>CN(C=O)C>[CH3:17][N:7]1[C:6]2[CH2:5][CH2:4][CH:3]([CH2:2][N:20]3[CH:21]=[CH:22][N:23]=[C:19]3[CH3:18])[C:15](=[O:16])[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: Cn1c2c(c3ccccc31)C(=O)C(CCl)CC2
Reactant: Cc1ncc[nH]1
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of 3-(chloromethyl)-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (0.50 g) and 2-methyl-1H-imidazole (1.60 g) in dry DMF was stirred under nitrogen at 90° for 3.75 h, and then poured onto water (25 ml). The suspension was stirred for 1 h, and the solid filtered off, washed with water (3×20 ml) and dried in vacuo at 50°. Column chromatography of this solid (0.53 g) eluting with a mixture of dichloromethane, ethanol and 0.88 aqueous ammonia (150:10:1) afforded the title compound (0.45 g) m.p. 228°-229°. This material was identical to the product from Example 7 by t.l.c. and n.m.r.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[NH3:18]>C(Cl)Cl.C(OCC)(=O)C>[NH2:18][S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3]
Reactant: N
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](CS(N)(=O)=O)C(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1.22 g of benzyl 3-chlorosulfonyl-2(R)-methylpropionate in 15 mL CH2Cl2 and cooled to −78° C. To this solution was added to 10 mL of liquid ammonia at −78° C. After 20 minutes the reaction was warmed to room temperature, concentrated in vacuo to afford a white solid. The solid was slurried in ethyl acetate, filtered to remove inorganic salts and concentrated in vacuo to afford 1.08 g of benzyl 3-aminosulfonyl-2(R)-methylpropionate as a clear yellow oil. The crude product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C[O:17][CH:18](O)[C:19]([F:22])([F:21])[F:20]>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:18]([OH:17])[C:19]([F:22])([F:21])[F:20]
Reactant: Cn1ccc(=O)c(O)c1
Reactant: COC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A mixture of 3-hydroxy-1-methyl-1H-pyridin-4-one (7.60 g, 60.7 mmol) and K2CO3 (0.84 g, 6.07 mmol) in trifluoroacetaldehyde methyl hemiacetal (26 mL) was sealed in a parallel reactor and stirred for overnight at 120° C. The reaction mixture was evaporated to dryness, and the residue was purified by flash column chromatography on silica gel using a mixture of isopropyl alcohol and a conc. NH4OH solution (80/20, v/v) as eluant. Pure fractions were combined together and evaporated to give the title compound as a white solid (2.32 g, 17% yield). HPLC purity (peak area percent) of this compound is 99% at λ=254 nm. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.59 (d, J=7.2 Hz, 1H), 6.20 (d, J=7.4 Hz, 1H), 5.80 (q, J=8.5 Hz, 1H) and 3.83 (s, 3H); MS-ESI (m/z): 223.7 [M+1]+, 206, 158. Other fractions were combined to give a second crop of the product (8.26 g, 61% yield). HPLC purity (peak area percent) of this compound is 98% at λ=254 nm. HPLC method: Column: Waters Symmetry C18; 5 μm, 3.9×150 mm; Mobile phase: A=the aqueous phase: 0.035% HClO4 pH 2.5; B=the organic phase: CH3CN; gradient: % B: 0 min—10%, 10 min—90%, 12 min—90%, 15 min—10%; flow rate: 1 mL/min; wavelength: 220, 254, 280 nm.
Reaction SMILES: Cl[C:2]1[N:3]2[C:7]([N:8]=[C:9]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11][C:10]=13)=[CH:6][CH:5]=[N:4]2.[NH:17]1[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]1.CCN(C(C)C)C(C)C>C(O)C>[CH3:16][N:13]1[CH2:12][CH2:11][C:10]2=[C:2]([N:17]3[CH2:20][CH:19]([C:21]([OH:23])=[O:22])[CH2:18]3)[N:3]3[C:7]([N:8]=[C:9]2[CH2:15][CH2:14]1)=[CH:6][CH:5]=[N:4]3
Reactant: CN1CCc2nc3ccnn3c(Cl)c2CC1
Reactant: O=C(O)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Temperature: 75 °C

Procedure:
To 1.77 g (7.48 mmol) 10-Chloro-7-methyl-6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene in 50 mL ethanol was added 0.83 g (8.22 mmol) 3-azetidinecarboxylic acid and 2.75 mL (15.7 mmol) DIPEA and the reaction mixture was heated at 75° C. for 4 hours. The mixture was concentrated and treated with diethyl ether and methanol. After ultrasound irradiation, a precipitate formed which was collected by filtration. The remaining solution was concentrated and the above mentioned procedure was repeated. The precipitates were combined and dried to yield the desired product as the DIPEA-salt.
Reaction SMILES: [C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:31])[CH3:30])[C:13]([O:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2].C(N(CC)CC)C.[C:40]1([CH2:46][C:47](Cl)=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([CH:5]1[O:11][CH:10]2[C:7]([C:47](=[O:48])[CH2:46][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:8](=[O:32])[N:9]2[C:12](=[C:29]([CH3:30])[CH3:31])[C:13]([O:15][CH:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COC(=O)C1NC2C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1NC2(C(=O)Cc3ccccc3)C(=O)N(C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 16.46 g of diphenylmethyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 160 ml of methylene chloride are added 9.6 ml of triethylamine and 9 ml of phenylacetyl chloride under ice-cooling, and the mixture stirred at room temperature for 2 hours. The reaction mixture is then washed with water, dried on magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 200 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 17 to 19 g of diphenylmethyl α-(3ξ-carbomethoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 80 to 90% yield.
Reaction SMILES: BrCC(NCC(N(C1C(Cl)=C(C(Cl)=CC=1)CO[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[N:24]=[C:23]([CH3:26])[CH:22]=[CH:21]2)C)=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:26][C:23]1[CH:22]=[CH:21][C:20]2[C:25](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:24]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)CBr)c3Cl)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 114.6 %

Procedure:
A mixture of 8-[3-[N-(bromoacetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (80 mg) 5-amino-1,3,4-thiadiazole-2-thiol (24 mg), potassium carbonate (42 mg) in dimethylformamide (2 ml) was stirred for 30 minutes at ambient temperature. To the mixture was added water, and the mixture was extracted with ethyl acetate twice. Combined organic layers were washed with water three times, dried over magnesium sulfate and concentrated. The residue was pulverized from diethyl ether to give 8-[3-[N-(5-amino-1,3,4-thiadiazol-2-ylthio)acetylglycol]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (25 mg) as a solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].[CH2:21](O)[CH3:22]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([O:19][CH2:21][CH3:22])=[O:18]
Reactant: CC(C(=O)O)c1ccc2c(c1)CCc1ccccc1O2
Reactant: CCO
Product: CCOC(=O)C(C)c1ccc2c(c1)CCc1ccccc1O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
An amount of 190 mg of 2-(10,11-dihydro dibenzo[b,f]-oxepin-2-yl)-propionic acid was dissolved in 5 ml of ethanol containing 10% hydrogen chloride and the resulting mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off to obtain the residue, which was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain pale brown oil, which was chromatographed over silica gel, eluted with benzene, and there was obtained 185 mg of ethyl 2-(10,11-dihydro dibenzo-[b,f]oxepin-2-yl)-propionate as pale yellow oil.
Reaction SMILES: [OH-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=O)[CH:10]=[CH:11][C:12]([OH:14])=[O:13].[NH2:16][NH2:17]>CO>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH2:10][CH:11]([C:12]([OH:14])=[O:13])[NH:17][N:16]=1
Reactant: NN
Reactant: O=C(O)C=CC(=O)c1ccccn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC(c2ccccn2)=NN1

Procedure:
Potassium hydroxide (3.29 g) is dissolved in 250 ml of methanol and 8.85 g of 4-(2-pyridyl)-4-oxo-2-butenoic acid is added. Hydrazine (1.6 g) is then added and the solution is heated at reflux temperature for 5 hours. Solvent is removed in vacuo and the residue is dissolved in 50 ml of water and treated with 3.0 g of acetic acid yielding the title compound.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=O)(C)(C)C.[C:24]([N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH:30]([CH3:35])[C:29]1=[O:36])([CH3:27])([CH3:26])[CH3:25]>>[NH2:8][C@H:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([N:31]1[CH2:32][CH2:33][CH2:34][N:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[C:29](=[O:36])[C@H:30]1[CH3:35])=[O:13]
Reactant: CC1NCCCN(C(C)(C)C)C1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Product: C[C@@H]1C(=O)N(C(C)(C)C)CCCN1C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared from (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid and 1-tert-butyl-hexahydro-3-methyl-2H-1,4-diazepin-2-one by the method described in Example 3, Step C and D. LC/MS 400.1 (M+1).
Reaction SMILES: Br.Br[CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1.[OH-:22].[Na+]>O>[OH:22][CH:3]1[C:8]([C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[CH:11][C:10]=2[O:19][CH3:20])=[CH:7][CH2:6][N:5]([CH3:21])[CH2:4]1
Reactant: [OH-]
Reactant: COc1cc(OC)c(C2=CCN(C)CC2Br)c(OC)c1
Agent: Br
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c(C2=CCN(C)CC2O)c(OC)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
50 g (0.118 mol of 3(R,S)-bromo-1-methyl-4-(2,4,6-trimethoxyphenyl)-1,2,3,6-tetrahydropyridine hydrobromide (VI) were heated under reflux for 2 h in 100 ml of water. The reaction mixture was then cooled to 20° C. and adjusted to pH 12.5 by dropwise addition of 30 ml of 30% strength sodium hydroxide solution. After a short time, a pale brown precipitate crystallized out. The mixture was stirred at 5-10° C. for a further 1 h, and the precipitated product was filtered off with suction and washed with 30 ml of water. The crude product was then stirred with 20 ml of acetone, filtered off with suction and dried in vacuo.
Reaction SMILES: [CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[NH:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([NH:7][C:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([Cl:21])=[CH:15][C:16]=2[CH3:20])[N:11]1[CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O
Reactant: CCCCI
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)n1c(=O)c2c(C)cc(Cl)nc2n1CCCC

Procedure:
In analogy to example 2, 100 mg (0.32 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid hexylamide were reacted with 59.2 mg (0.32 mmol) of 1-iodobutane in DMF with triethylamine at RT. Yield: 23 mg (19%), M+H+: 367.27.