Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][O:11][C:12]([CH2:14][C:15](=[CH2:19])[C:16]([O-:18])=[O:17])=[O:13].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:19][CH:15]([CH2:14][C:12]([O:11][CH3:10])=[O:13])[C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: C=C(CC(=O)OC)C(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(CSc1ccc(Cl)c(Cl)c1)C(=O)O

Procedure:
A mixture of 3,4-dichlorobenzenethiol (1.15 ml), sodium 3-methoxycarbonyl-2-methylenepropionate (1.50 g), methanol (40 ml), and triton B (40% methanol solution, 5 drops) was refluxed for 20 hours. The reaction mixture was concentrated in vacuo. To the resulting residue was added a diluted hydrochloric acid, and a separated oil was extracted with diethyl ether. The organic layer was washed with water, dried over MgSO4, and evaporated at reduced pressure. The residue was purified by flash column chromatography on silica by eluting with chloroform/ethanol (10:1) to give 2.34 g of 3-(3,4-dichlorophenylthio)-2-methoxycarbonylmethylpropionic acid as an oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2ccccc2)n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
A stirred solution, cooled in ice, of 0.25 ml (0.48 ml) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution of 100 mg (0.26 mmol) of 5-(2,6-dichlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine and 0.1 ml (0.7 mmol) of triethylamine in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for 3 days. 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution were added, the phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 110 mg (100%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][CH:13]([CH2:16][CH3:17])[CH:14]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][CH2:12][CH:13]([CH3:14])[CH2:16][CH3:17])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CCC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCC(C)CNc1ccc(Cl)cc1C(=O)O

Procedure:
5-chloro-2-(2-methyl-butylamino)-benzoic acid was prepared from 2-amino-5-chloro-benzoic acid (23.31 mmol, 4.0 g) and 2-methylbutyraldehyde (23.31 mmol, 2.0 g) with sodium triacetoxyborohydride (96.62 mmol, 9.88 g) as per Procedure G (5.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19](OCC)=[O:20])[C:5]2=[O:24].[NH3:25]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([NH2:25])=[O:20])[C:5]2=[O:24]
Reactant: N
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Solvent: CO
Product: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Temperature: 150 °C
Yield: 95 %

Procedure:
Compound D (1.00 g, 2.56 mmol, 1.00 eq) was suspended in 7N ammonia in methanol (30 mL) in a microwave vial and the reaction was heated in a microwave reactor at 150° C. for 60 minutes. The reaction was concentrated to afford 881 mg (95%) of the title compound as a brown solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J=4.0 Hz, 1H), 8.57 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 7.85 (dd, J=9.1, 2.4 Hz, 1H), 7.77-7.73 (m, 2H), 7.66 (d, J=4.1 Hz, 1H), 7.56-7.50 (m, 2H), 7.02 (d, J=9.1 Hz, 1H); ES-MS [M+1]+: 361.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH2:16](OC(C1NC2C(C=1)=CC=CC=2)=O)C>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(F)ccc2n1C
Yield: 100 %

Procedure:
According to the procedure of Preparation 1(a), except substituting ethyl 5-fluoro-indole-2-carboxylate for the ethyl-indole-2-carboxylate, the title compound (3.3 g, 100%) was prepared as a white solid: MS (ES) m/e 222 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[S:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH2:32])([O-:24])=[O:23].C(=O)([O-])O.[K+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[N+:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]1[O:1][N:2]=[C:3]([C:4]2[N:5]=[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]3)[S:7][CH:8]=2)[CH2:32]1)([O-:24])=[O:23]
Reactant: C=Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=NO)cs2)CC1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4[N+](=O)[O-])C3)cs2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{4-[(hydroxyimino)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.80 g) and 1-nitro-2-vinylbenzene (1.60 g) in ethyl acetate (50 ml) were added, at room temperature, potassium hydrogencarbonate (4.50 g) and N-chlorosuccinimide (1.44 g) and then one drop of water. After stirring at 60° C. overnight, the reaction mixture was admixed with ethyl acetate and water and extracted with ethyl acetate. The organic extracts were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography. This gave tert-butyl 4-{4-[5-(2-nitrophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (2.10 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[CH:10]=2)[CH2:7][CH2:6]1)=[O:4].C(OCC)(=O)C>C(O)C>[CH3:1][O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([F:18])[CH:10]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(Oc2ccc([N+](=O)[O-])c(F)c2)CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C1(Oc2ccc(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 4.49 g (17.6 mmol) 1-(3-fluoro-4-nitro-phenoxy)-cyclopropanecarboxylic acid methyl ester in 50 mL ethanol 0.5 g 10% palladium on charcoal was added and the suspension stirred for 8 h at room temperature under an atmosphere of hydrogen (1.7 bar). After the addition of 100 mL ethyl acetate the catalyst was filtered off, the filtrate evaporated and dried under high vacuum to give the title compound as a brown oil (98%) which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O-:18].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:18][CH3:17])=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: COc1cc2nc(N)c(Cl)nc2cc1OC
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc2nc(N)c(OC)nc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
To 2-amino-3-chloro-6,7-dimethoxy quinoxaline (3.27 g, 13.6 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (4.41 g, 20.4 mmol) in methanol was added at room temperature and stirred further at room temperature for 2 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 2.73 g of the titled compound (yield, 85%).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:3]=1.[Cl-].[CH3:19][C:20]1[N:25]2[N:26]=[C:27]([CH2:29][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:28]=[C:24]2[C:23]([CH3:49])=[N:22][CH:21]=1>>[Br:1][C:2]1[N:6]=[C:5]([CH:7]=[CH:29][C:27]2[N:28]=[C:24]3[C:23]([CH3:49])=[N:22][CH:21]=[C:20]([CH3:19])[N:25]3[N:26]=2)[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(Br)nc2C=O)cc1
Reactant: Cc1ncc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Product: COc1ccc(Cn2nc(Br)nc2C=Cc2nc3c(C)ncc(C)n3n2)cc1
Yield: 67.2 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 1g) using 3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole-5-carbaldehyde (50 mg, 169 μmol, Eq: 1.00) and ((5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphonium chloride (77.5 mg, 169 μmol, Eq: 1.00) as starting materials. Chromatography afforded 2-{2-[5-Bromo-2-(4-methoxy-benzyl)-2H-[1,2,4]triazol-3-yl]-vinyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (50 mg, 35.4%) as a white solid. MS: m/z=442.3 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:12]O.[CH:20]([NH:23][CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]>>[CH:20]([N:23]([CH2:12][CH2:11][CH:10]([C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:24]([CH3:26])[CH3:25])([CH3:22])[CH3:21]
Reactant: COc1ccc(C)cc1C(CCO)c1ccccc1
Reactant: CC(C)NC(C)C
Product: COc1ccc(C)cc1C(CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
U.S. Pat. No. 6,822,119 provides another alternate method for the preparation of tolterodine. The process involves reacting 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one with dimethyl sulphate in the presence of sodium hydroxide, and a phase transfer catalyst to obtain methyl-3-(2-methoxy-5-methylphenyl)-3-phenyl propionate. Reducing the ester thus obtained with a reducing agent in the presence of a Lewis acid to obtain 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol. Protecting the hydroxy group of the alcohol to followed by aminating with diisopropylamine to give N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropylamine and removing the hydroxy protecting group to obtain N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine of Formula I.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.C[Si]([N:46]=[C:47]=[O:48])(C)C>C(Cl)Cl>[NH2:46][C:47]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[O:48]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3NC(N)=O)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.8 %

Procedure:
A solution of 445 mg (0.80 mmol) of N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) in 3 mL of methylene chloride under a nitrogen atmosphere was treated with 4 mL (29.5 mmol) of trimethylsilyl isocyanate. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under vacuum and the residue was passed over silica gel. Elution with ethyl acetateexanes (4:1) yielded 211 mg (0.35 mmol, 44%) of product. FAB-MS: calculated for C34H41N5O5 599: found 622 (M+Na). 1H NMR (400 MHz, CDCl3): δ 1.31 (s, 3H), 1.38 (s, 3H), 1.39 (s, 9H), 1.90 (m, 1H), 2.48 (dd, 2H), 2.60 (m, 2H), 4.48 (m, 1H), 4.95 (d, 1H), 5.08 (d, 1H), 5.28 (br s, 1H), 6.66 (br s, 1H), 6.78 (d, 1H), 7.22 (m, 11H), 7.72 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]([CH3:28])=[N:26][C:25]([NH2:29])=[N:24]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27]([CH3:28])=[N:26][C:25]([NH:29][C:2]3[CH:3]=[CH:4][C:5]([N:10]4[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]4)=[C:6]([CH:9]=3)[C:7]#[N:8])=[N:24]2)=[CH:21][CH:22]=1
Reactant: Cc1nc(N)nn1-c1ccc(F)cc1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3nc(C)n(-c4ccc(F)cc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(4-fluoro-phenyl)-5-methyl-1H-[1,2,4]triazol-3-ylamine (prepared in analogy to Gazzetta Chimica Italiana 29, 105 (1899)). The title compound was obtained as a slightly brownish solid (Yield=24%). MS ISP (m/e): 374.1 (100) [(M+H)+].
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[CH:10]=[C:9]([Cl:19])[CH:8]=1)[CH3:6].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2([CH2:43][OH:44])[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>ClCCl.C1CCCCC1>[Cl:19][C:9]1[CH:8]=[C:7]([CH:5]([O:44][CH2:43][C:30]2([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][CH:28]=3)[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35]2)[CH3:6])[C:15]2[C:11](=[CH:12][N:13]([CH:16]3[CH2:18][CH2:17]3)[N:14]=2)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(Cl)cc2cn(C3CC3)nc12
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(C3CC3)nc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-1-(5-Chloro-2-cyclopropyl-2H-indazol-7-yl)ethyl 2,2,2-trichloroacetimidate (365 mg, 0.96 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (366 mg, 1.05 mmol) were combined in a dichloromethane/cyclohexane mixture (1:1, 10 mL) and cooled to 0° C. The reaction was treated with tetrafluoroboric acid-diethyl ether complex (26 μL, 0.19 mmol), stirred at 0° C. for 1 h, quenched by addition of saturated sodium bicarbonate and diluted with diethyl ether. The layers were separated. The ethereal was washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (18% ethyl acetate/hexanes) gave 0.32 g (62%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.86 (s, 1H), 7.40 (m, 1H), 7.28-7.31 (m, 2H), 6.99-7.03 (m, 2H), 6.75 (m, 1H), 4.90 (q, J=6.4 Hz, 1H), 3.86-3.90(m, 2H), 3.32-3.36 (m, 2H), 3.00-3.09 (m, 2H), 2.04-2.17 (m, 2H), 1.84-1.95 (m, 2H), 1.43 (s, 9H), 1.41 (d, J=6.4 Hz, 3H), 1.26-1.30 (m, 2H), 1.12-1.16 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 163.7, 161.4 (d, J=244.7 Hz), 152.2, 145.3, 138.9, 135.1, 128.9, 127.7, 122.3, 117.2, 115.2, 115.1, 79.5, 77.8, 73.9, 60.5, 41.3, 34.7, 28.6, 22.7, 14.3, 7.4. Mass spec.: 528.62 (MH)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]1=[O:18].C(N(C(C)C)CC)(C)C.[N:29]([CH2:32][C:33]([O:35]CC)=[O:34])=[C:30]=[O:31]>ClCCl>[OH:11][C:10]1[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6](=[O:18])[N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:8](=[O:12])[C:9]=1[C:30]([NH:29][CH2:32][C:33]([OH:35])=[O:34])=[O:31]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(C)CCN1C(=O)CC(=O)N(CCC(C)C)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CCn1c(O)c(C(=O)NCC(=O)O)c(=O)n(CCC(C)C)c1=O
Reaction time: 5 h

Procedure:
-{[6-Hydroxy-1,3-bis(3-methylbutyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. A mixture of 1,3-bis(3-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione (1.2 g, 4.47 mmoles) and diisopropylethylamine (1.56 mL, 8.94 mmoles) was stirred in dichloromethane (30 mL) and treated with ethyl isocyanatoacetate (501 uL, 4.47 mmoles). The mixture was stirred for 5 hours, washed with 1 molar hydrochloric acid (×2), evaporated, taken up in ethanol-6 molar sodium hydroxide and stirred overnight. The mixture was acidified and extracted into ethyl acetate (×2). The extracts were washed with 1 molar hydrochloric acid evaporated, dried and evaporated. The title compound was recrystallized from acetic acid (430 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.09 (br. s, 1 H), 10.11 (s, 1 H), 4.09-4.16 (m, 2 H), 3.77-3.86 (m, 4 H), 1.51-1.62 (dt, J=13.29, 6.59, 6.59, 6.59, 6.59 Hz, 2 H), 1.42 (q, J=7.07 Hz, 4 H), 0.91 (d, J=6.57 Hz, 12 H).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([NH:15][NH2:16])=[O:14])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25]([C:27](=O)[CH3:28])[CH:26]=1>CO.C(O)(=O)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:30])=[C:25](/[C:27](=[N:16]/[NH:15][C:13](=[O:14])[C:12]2[CH:17]=[CH:18][CH:19]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)/[CH3:28])[CH:26]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 54.1 %

Procedure:
3-(piperidin-1-ylsulfonyl)benzohydrazide (65 mg, 0.229 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (39.1 mg, 0.229 mmol) was dissolved in methanol (Volume: 4 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the product (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-3-(piperidin-1-ylsulfonyl)benzohydrazide (55 mg, 0.124 mmol, 53.9% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.09 (m, 2H), 7.85 (d, 1H, J=8.0 Hz), 7.62 (t, 1H, J=8.0 Hz), 7.41 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=8.0 Hz), 6.93 (d, 1H, J=8.8 Hz), 2.97 (m, 4H), 2.41 (s, 3H), 1.61 (m, 4H), 1.40 (m, 2H). Mass [M+H]+:436.9
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.[Cl:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH: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)=[O:28]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1cccc(C(=O)O)c1Cl
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C)c2Cl)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 2-Chloro-3-methyl-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].N1CCCC1>>[C:15]([O:14][C:12]([N:19]1[CH2:24][CH2:23][C:22]2([NH:9][C:7](=[O:8])[C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:11]2)[CH2:21][CH2:20]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: NC(=O)c1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(Br)ccc1O2
Temperature: 72 °C
Yield: 250.3 %

Procedure:
Three batches of 5-bromo salicylamide (5.00 g each, 23.1 mmol), N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) and pyrrolidine (1.64 g, 23.1 mmol) were heated in different flasks at 72° C. under MW irradiation for 1 h. Further N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) was added and the mixtures were heated for 1 h at 72° C. The resulting precipitates were collected by filtration and washed with MeOH to give 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester (17.2 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][NH:32][C:33]([NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49]O)=[CH:45][CH:44]=1)=[O:34]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:49][C:46]2[CH:45]=[CH:44][C:43]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[CH2:36][NH:35][C:33]([NH:32][CH3:31])=[O:34])=[CH:48][CH:47]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CO)cc1
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step D) and 2'-[[(methylamino)carbonyl]amino]methyl-1,1'-biphenyl-4-methanol, methanesulfonate ester (Step I) according to the procedure described in Example 35, Step H. 1H NMR (200 MHz, CDCl3): δ 1.33 (s,6H), 1.78 (m, 1H), 2.37-2.63 (m, 3H), 2.60 (d, 5 Hz, 3H), 4.20 (d, 6 Hz, 2H), 4.52 (m, 2H), 4.72 (t, 6 Hz, 1H), 4.86 (d, 16 Hz, 1H), 4.89 (s, 2H), 5.10 (d, 15 Hz, 1H), 5.69 (s, 1H), 6.73 (d, 7.5 Hz, 1H), 7.08-7.35 (m, 16H) 7.40 (m, 1H). FAB-MS: calculated for C39H43N5 O5 661; found 662 (M+H, 40%).