Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[C:1]1([CH2:7][CH2:8][NH:9][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1ccccc1)c1ccccc1Br

Procedure:
A mixture of 62.7 ml (500 mmol) of phenylethylamine, 70.4 ml (506 mmol) of triethylamine and 150 ml of dichloromethane was admixed dropwise at 0° C. with a solution of 109.2 g of 2-bromobenzoyl chloride in 50 ml of dichloromethane with good stirring at such a rate that the temperature did not exceed 30° C. Subsequently, the mixture was stirred at room temperature for a further 1 h. The colorless solid thus obtained was filtered off with suction, washed three times with 200 ml of dichloromethane and dried under reduced pressure. The yield at a purity of approx. 99.0% was 138.2 g (453 mmol), 90.7% of theory.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[S:14][C:15]([S:18][CH3:19])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2].[OH:37]OS([O-])=O.[K+]>CC(C)=O.O>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[S:14][C:15]([S:18]([CH3:19])=[O:37])=[N:16][N:17]=3)[CH:12]=[C:6]2[C:5]=1[NH:20][C@@H:21]1[CH2:25][CH2:24][C@@:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:26])[C:22]1([CH3:36])[CH3:35])(=[O:3])[NH2:2]
Reactant: CSc1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)s1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CC[C@](C)(NC(=O)OC(C)(C)C)C4(C)C)c(C(N)=O)cnn3c2)s1
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
A solution of tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylthio)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (306.2 mg, 0.576 mmol) and oxone (531 mg, 0.864 mmol) in acetone (3 mL) and water (3 mL) was stirred at RT for 4 hrs. The reaction mixture was diluted with 30 mL of water which was stirred for 30 minutes. The solid was collected to give the desired tert-butyl ((1S,3R)-3-((3-carbamoyl-6-(5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)carbamate (264.5 mg, 77% yield). MS (ES+) m/z: 548.08 (M+H); HPLC retention time: 3.296 min (analytical HPLC Method F).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl.[CH3:31][NH:32][O:33][CH3:34].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C>CN(C)C=O.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[C:10](=[O:12])[N:32]([O:33][CH3:34])[CH3:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6.00 g (19.76 mmol) rac-tert-butoxycarbonylamino-(4-chloro-3-fluoro-phenyl)-acetic acid in 146 ml dimethylformamide were added 20.71 ml (118.6 mmol) N-ethyl-diisopropylamine, 2.07 g (20.75 mmol) N,O-dimethylhydroxylamine hydrochloride and 8.26 g (24.70 mmol) 0-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and the solution stirred at ambient temperature for 30 min. The reaction mixture was diluted with water and the resulting suspension stirred for 15 min. The precipitate was filtered and washed with water and dried: 5.18 g rac-[(4-chloro-3-fluoro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester as colorless solid: MS (ISP): 347.2 (M+H)+ and 247.1 ((M-Boc)+H)+ (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: O=C(O)CC1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1CCc2cc(Cl)cc3[nH]c(=O)c(=O)n1c23)Nc1ccccc1
Yield: 59.7 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-chloro-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (200 mg, 0.68 mmol) and aniline (200 mg, 2.15 mmol) to give 150 mg of the title compound (60%):mp >280° C.; 1H NMR (270 MHz, DMSO-d6) δ12.09 (bs, 1H), 10.02 (s, 1H), 7.57 (d, 2H, J=7.8 Hz), 7.30 (t, 2H, J=7.8 Hz), 7.14 (s, 1H), 7.06 (t, 1H, J=7.8 Hz), 7.05 (s, 1H), 5.14~5.29 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=17.1 Hz), 2.55~2.70 (m, 2H), 2.10 (dm, 1H, J=13.5 Hz), 1.80~1.96 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[S:14][C:13]([C:15](OC)=[O:16])=[C:12]([O:19][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]=4[Cl:29])[CH3:21])[CH:11]=3)[C:6]=2[CH:30]=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/[N:66]=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:31])=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[S:14][C:13]([C:15]([NH2:66])=[O:16])=[C:12]([O:19][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH:36]5[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]5)[C:23]=4[Cl:29])[CH3:21])[CH:11]=3)[C:6]=2[CH:30]=1
Reactant: CN1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Reactant: COC(=O)c1sc(-n2cnc3cc(F)c(Cl)cc32)cc1O[C@H](C)c1cccc(O)c1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cc(F)c(Cl)cc32)sc1C(N)=O)c1cccc(OC2CCN(C)CC2)c1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 608.5 %

Procedure:
To a solution of methyl 5-(6-chloro-5-fluoro-1H-benzimidazol-1-yl)-3-{[(1R)-1-(2-chloro-3-hydroxyphenyl)ethyl]oxy}-2-thiophenecarboxylate (Example 69, Step E, 0.10 g, 0.21 mmol) and 1-methyl-4-piperidinol (0.05 g, 0.42 mmol) in DCM (2 mL) was added polymer-supported triphenylphosphine (0.19 g, 0.42 mmol), di-tert-butylazodicarboxylate (0.10 g, 0.42 mmol). The reaction mixture was stirred for 8 h. The reaction was filtered with DCM washings and the volatiles were evaporated under reduced pressure. To the residue was added a solution of 7 N ammonia in MeOH (8 mL). The mixture was heated in a sealed tube to 70° C. for 48 h and then cooled to rt. Silica; was added and the volatiles evaporated under reduced pressure and the residue was purified by flash chromatography ((0 to 100% 89/10/1 DCM/MeOH/ammonium hydroxide:DCM) to afford 0.72 g (61%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.86 (d, J=9.7 Hz, 1H), 7.84 (s, 1H), 7.72 (d, J=6.4 Hz, 1H), 7.33 (t, J=8.0 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.17 (s, 1H), 7.15 (d, J=8.2 Hz, 1H), 7.13 (s, 1H), 6.00 (q, J=6.0 Hz, 1H), 4.45 (s, 1H), 2.51-2.62 (m, 2H), 2.15-2.25 (m, 2H), 2.13 (s, 3H), 1.78-1.93 (m, 2H), 1.70 (d, J=6.4 Hz, 3H), 1.56-1.67 (m, 2H). MS (ESI): 564 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1([CH2:8][CH2:9][CH2:10][N:11]2[C:15](=[O:16])[CH2:14][S:13][CH:12]2[CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CC#CC2(O)CCCCC2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCCC2(O)CCCCC2)cc1

Procedure:
4-{3-[3-[3-(1-Hydroxycyclohexyl)-2-propynyl]-4-oxo-2-thiazolidinyl]propyl}benzoic Acid (4.0 g., 0.01 mole) is dissolved in ethyl acetate (45 ml.) and hydrogenated at 25° C. and one atmosphere pressure over 1.0 g. of a 5% palladium on charcoal catalyst. When 0.01 mole of hydrogen is absorbed (2 hours), uptake of hydrogen becomes very slow. An additional 1.5 g. of catalyst is added and hydrogenation continued for 70 hours until 0.02 mole of hydrogen has been absorbed. The catalyst is removed by filtration and the solvent evaporated. The residual oil is chromatographed on silica gel with elution by 2% methanol in chloroform. The chromatographed product crystalizes when triturated with ether. There is obtained 1.2 g. of the title product, m.p. 118°-121° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:11])([O-:10])[O-:9].[Pb+2:12]>O>[O:7]([Pb:12][O:11][C:8]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:10])=[O:9]
Reactant: [Pb+2]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1
Solvent: O
Product: O=C=O
Product: c1ccc(O[Pb]Oc2ccccc2)cc1
Temperature: 180 °C

Procedure:
Then, 1.021 kg of PhOH was charged into reaction vessel 50 and stirred at 180° C. (as measured at the jacket) under atmospheric pressure, to thereby effect a reaction. During the reaction, unreacted PhOH was distilled off from the top of distillation column 54 disposed on reaction vessel 50 at a rate of 0.1 kg/hr through conduit 55A. Thus, in reaction vessel 50, a reaction proceeded in which lead(II) carbonate reacts with PhOH to form diphenoxy lead, carbon dioxide and water. The carbon dioxide and water formed in the above reaction were withdrawn from the reaction vessel together with the unreacted PhOH distilled off. A reaction mixture, which remained in reaction vessel 50 after performing the above reaction for 2 hours, was withdrawn from reaction vessel 50 and transferred through conduit 46 and introduced into storage vessel 47.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](OCC)(OCC)OCC.[NH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([OH:32])[CH:23]=1>CC(O)C>[CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[C:6](=[CH:11][NH:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([OH:32])[CH:23]=2)[C:4](=[O:5])[O:3]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(=O)c1ccc(N)cc1O
Reactant: CCOC(OCC)OCC
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Temperature: 100 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
After adding Meldrum acid (7.2 g, 50 mmol), triethyl orthoformate (50 ml) and 2-propanol (50 ml) to the publicly known compound methyl 4-amino-2-hydroxybenzoate (7.59 g, 45.4 mmol), the mixture was stirred at 100° C. for 1 hour. Upon cooling to room temperature, the precipitated crystals were filtered out, washed with diethyl ether and blow-dried to obtain the title compound (13.98 g, 43.5 mmol, 95.8%) as white crystals.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[CH:35]=[CH:34][N:33]=[C:27]2[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[S:28][C:27]3=[N:33][CH:34]=[CH:35][N:26]3[C:25]=2[CH3:24])=[O:31])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1c(C(=O)O)sc2nccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2sc3nccn3c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Methyl-imidazo[2,1-b]thiazole-2-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=492.3.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:10]=2)[NH:5][C:4](=[O:28])[CH:3]=1.[OH:29]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[O:29])[CH:10]=2)[NH:5][C:4](=[O:28])[CH:3]=1
Reactant: OO
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccc4ccccc4n3)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccc4ccccc4n3)cc12

Procedure:
Prepared analogous to Example 123 from 4-methyl-6-[4-(2-quinolyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.O.[CH3:17][N:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([N:18]([CH3:19])[CH3:17])=[N:21][CH:22]=2)[C:11]=1[CH3:12]
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N(C)C)nc2)nc2cc(F)cc(F)c2c1Cl

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-(N,N-dimethylamino)pyridine-5-boronic acid hydrate (0.335 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 1.3 h to give 5-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-N,N-dimethylpyridin-2-amine as a yellow solid. Mass Spectrum (ESI) m/e=344.1 (M+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([N:27]3[C:31](=[O:32])[NH:30][N:29]=[N:28]3)[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=[O:7].[C:45](=O)([O-])[O-].[K+].[K+].IC>>[CH3:44][Si:2]([CH3:43])([CH3:1])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([N:27]3[C:31](=[O:32])[N:30]([CH3:45])[N:29]=[N:28]3)[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=[O:7]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(-n4nn[nH]c4=O)c(Cl)cc3[nH]c2=O)c1
Agent: [K+]
Solvent: CI
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(-n4nnn(C)c4=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(5-oxo-4,5-dihydro-tetrazol-1-yl) -1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (35 mg in 2 mL dry N,N-dimethylformamide) was added 26 mg of finely powdered potassium carbonate followed by 0.011 mL iodomethane and the mixture stirred at room temperature. After 30 minutes, the reaction was quenched by the addition of saturated ammonium chloride and the mixture partitioned between ethyl acetate and water. The organic layer was isolated and washed with water and brine, then dried over sodium sulfate. Purification of the concentrate by preparative tlc on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (21 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10][C:9]2=[O:20].CN(C)C1C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10][C:9]2=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCC(=O)N1CCC(=O)c2cc(N)ccc21
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCC(=O)N1CCC(=O)c2cc(NC(C)=O)ccc21
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
A solution of acetyl chloride (0.604 g) in methylene chloride (5 ml) was added dropwise to a solution of 6-amino-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.526 g) and N,N-dimethylaniline (1.016 g) in methylene chloride (15 ml) with ice cooling over a period of 10 minutes and stirred for further 20 minutes. The mixture was diluted with chloroform, washed successively with 10% hydrochloric acid, water, and brine, dried over magnesium sulfate, and evaporated in vacuo. The residual solid was recrystallized from methanol to give 6-acetamido-4-oxo-1-propionyl-1,2,3,4-tetrahydroquinoline (1.64 g).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH2:6]1)([OH:3])=[O:2].[Br:14]Br>C(Cl)Cl>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH2:6][CH:5]([CH2:4][C:1]([OH:3])=[O:2])[C:9]=2[CH:10]=1
Reactant: BrBr
Reactant: O=C(O)CC1COc2ccccc21
Solvent: ClCCl
Product: O=C(O)CC1COc2ccc(Br)cc21
Reaction time: 0.42 h

Procedure:
To a solution of 3-(carboxymethyl)-2,3-dihydro-benzofuran (reference example 16, 1.26 g, 7.7 mmol) in CH2Cl2 (24 mL) is added, dropwise, a solution of Br2 in CH2Cl2 (7 mL, 1 M). On complete addition the solution is stirred for a further 25 min. The reaction mixture is concentrated under vacuum to give the title compound (1.86 g) as a tan solid. 1H NMR (CDCl3) d 2.67 (dd, J=16, 8 Hz, 1H), 2.85 (dd, J=16, 6 Hz, 1H), 3.88 (m, 1H), 4.29 (t, J=8 Hz, 1H), 4.79 (t, J=8 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 7.26 (m, 2H). MS m/z 256/258 Br pattern (M+).
Reaction SMILES: Cl.[C:2]([NH:7][CH2:8][CH2:9][CH2:10][NH2:11])(=[O:6])[C:3]([CH3:5])=[CH2:4].O.[N:13]1[C:20]([Cl:21])=[N:19][C:17](Cl)=[N:16][C:14]=1[Cl:15].C(=O)(O)[O-].[Na+]>CC(C)=O>[C:2]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:17]1[N:19]=[C:20]([Cl:21])[N:13]=[C:14]([Cl:15])[N:16]=1)(=[O:6])[C:3]([CH3:5])=[CH2:4]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=C(C)C(=O)NCCCN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(=O)NCCCNc1nc(Cl)nc(Cl)n1
Temperature: 25 °C

Procedure:
To a solution of 71.6 g (0.4 mole) of 3-methacrylamidopropylamine hydrochloride in 400 ml. of water being stirred at 0°-5° C. was added dropwise a solution of 79 g (0.4 mole) of cyanuric chloride in 400 ml of acetone. To this mixture was then added in portions 67.2 g (0.8 mole) of sodium bicarbonate over the course of 1 hr. The mixture was stirred at room temperature for an additional hour and then 2 l of water was added. The product was collected by filtration and dried in vacuo at room temperature to yield 75.8 g. The product was recrystallized from 600 ml of ethyl acetate to give 53.2 g (46%) (mp 138°-140° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[F:19].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[F:19]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(N)c(F)c1
Temperature: 90 °C

Procedure:
Diethyl (4-amino-3-fluorophenyl)propanedioate (11.85 g, 44.1 mmol) was dissolved in ethanol (80 ml) and treated with NaOH (2.6 g, 1.5 eq) dissolved in 18 ml of water to give a pink solution. This was heated to 90° C. for 1 hour until complete. Heating continued for 1 further hour, and then cooled to room temperature. Solvent evaporated and acidified with 2N HCl. Extracted with ethyl acetate (3×100 ml). Organics washed with brine and dried over MgSO4. Evaporated to give the title compound as a yellow oil which crystallised slowly on standing (6.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)N(CC(=O)OCc3ccccc3)C(=O)C2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.300 g, 0.81 mmol), benzyl bromoacetate (0.236 g, 0.97 mmol), and potassium carbonate (0.335 g, 2.42 mmol) in DMF (5 mL) was stirred at 60° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give a pale yellow powder, which was re-crystallized from hexane and ethyl acetate to provide benzyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (0.474 g, 79%) as an off-white powder.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[CH:13][CH:14]=1
Reactant: OCc1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: OCc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1

Procedure:
4-Hydroxymethyl-phenol (1 g, 8.06 mmol), 1-Chloromethyl-4-trifluoromethyl-benzene (1.57 g, 8.06 mmol), and cesium carbonate (5.26 g, 16.12 mmol) were refluxed in acetonitrile for 20 h, cooled, filtered, and concentrated to give the title compound. MS m/z 265 (M−H2O+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11](C2C=CC(C(OC)=O)=CC=2)[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Br:18])=[CH:7][CH:6]=1)=[O:4].[C:30]([C:33]1[CH:49]=[CH:48][C:36]([CH2:37]NC2C=CC(C(O)=O)=CC=2)=[CH:35][CH:34]=1)([OH:32])=[O:31].[H-].[Na+].Br[CH2:53]CCCCC(Cl)=O>O(CCCC)CCCC>[CH3:53][O:32][C:30]([C:33]1[CH:49]=[CH:48][C:36]([CH2:37][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Br:18])=[CH:35][CH:34]=1)=[O:31]
Reactant: O=C(Cl)CCCCCBr
Reactant: COC(=O)c1ccc(N(C(=O)CCCCCBr)c2ccc(C(=O)OC)cc2)cc1
Reactant: O=C(O)c1ccc(CNc2ccc(C(=O)O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COC(=O)c1ccc(CN(C(=O)CCCCCBr)c2ccc(C(=O)OC)cc2)cc1
Yield: 91 %

Procedure:
Following the reaction instructions for the production of compound 19a, the amine 15b (856 mg, 2.86 mmol) is first added to a suspension of sodium hydride (60% in mineral oil; 126 mg, 3.15 mmol) in anhydrous n-Bu2O (12 ml) and the resulting mixture is then added with 6-bromohexanoic acid chloride (0.51 ml, 3.43 mmol). The crude product that is obtained after processing is purified through column chromatography (silica gel, ethyl acetate/petroleum ether 1:2). 1.24 g (91%) of compound 19b are obtained as a colorless. Melting point. 190-191° C.; IR (Film) 2970, 2920, 2840, 1705, 1645, 1590 cm−1; 1H-NMR (CDCl3) δ 8.02 (d, 8.6 Hz, 2H), 7.94 (d, 8.4 Hz, 2H), 7.25 (d, 8.4 Hz, 2H), 7.05 (d, 8.4 Hz, 2H), 4.95 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.36 (t, 6.7 Hz, 2H), 2.11 (t, 7.4 Hz, 2H), 1.85-1.72 (m, 2H), 1.71-1.57 (m, 2H), 1.42-1.29 (m, 2H); MS (FD) m/z 477 (M+ for Br81), 475 (M+ for Br79).