Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][NH2:11])[CH3:7].CC1C=C(C)N=C(S[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])N=1.Cl>O1CCOCC1.C(N(CC)CC)C>[C:24]([O:23][C:21]([NH:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:8][CH2:9][CH2:10][NH2:11])[CH3:7])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: CN(CCCN)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CN(CCCN)CCCNC(=O)OC(C)(C)C
Yield: 70.8 %

Procedure:
Into 180 ml of water, was dissolved 150 g of bis(3-aminopropyl)methylamine followed by 53 g of triethylamine. To the solution, while being cooled in ice and stirred, was added portionwise a solution of 83 g (1/3 equivalent) of 4,6-dimethyl-2-tert-butoxycarbonylthiopyrimidine in 200 ml of dioxane. The mixture was allowed to react at room temperature for 5 hours. The reaction mixture was stripped of the dioxane and triethyl amine by disillation under reduced pressure. The residue was adjusted to pH 2 with 6N hydrochloric acid and washed with chloroform. The aquoues layer was adjusted to pH 13.5 with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate and freed from the solvent by distillation under reduced pressure to yield 60 g (24% yield) of (3-tert-butoxycarbonylaminopropyl)-(3-aminopropyl)methylamine (BOC-APMP).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])(=O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:55])([CH3:57])[CH3:56])([CH3:53])[CH3:52])[CH:46]([O:58][CH2:59][CH:60]=[CH2:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:80]([C:83]([CH3:86])([CH3:85])[CH3:84])([CH3:82])[CH3:81])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(tert-butyldimethylsiloxy)-3"-allyloxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (165 mg) in dry methylene chloride (4 ml) was added an excess of 2,6-lutidine (41 μl) and the mixture was stirred at room temperature. After 10 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (49 μl) was added via syringe. After 1 hour the reaction mixture was diluted with ethyl acetate, extracted from saturated sodium bicarbonate, washed with brine and the organic phase dried over magnesium sulfate. Removal of the solvent in vacuo and flash chromatography on silica gel (ethyl acetate:hexane (1:4)+1% methanol) gave the title compound (130 mg).
Reaction SMILES: C[NH:2][C@@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH:18]1([CH2:24][CH:25]([CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[CH3:36]CN(CC)CC>C1COCC1.CCOC(C)=O>[CH3:36][C:25]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)([CH2:24][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:26]([NH:2][C@@:3]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:27]
Reactant: CCN(CC)CC
Reactant: CN[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)C(CC1CCCCC1)CC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CC1CCCCC1)(CC1CCCCC1)C(=O)N[C@](C)(Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 65 %

Procedure:
To a solution of 0.69 g (3.0 mmol) of methyl α-methyl-D-tryptophan in 20 mL THF was added 0.8 g (3.0 mmol) of bis-(cyclohexylmethyl)acetyl chloride followed by 0.5 mL of Et3N and the suspension stirred at room temperature for 3 days. The mixture was diluted with EtOAc and washed with 1N citric acid, H2O, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 1.4 g of the crude product as a foam. Chromatography on silica gel, eluting with CHCl3 /EtOAc (95/5) gave 0.91 g (65% yield) of the product as a white foam. The structure was confirmed by NMR and mass spectroscopy.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=O.O>C1C=CC=CC=1>[F:9][C:10]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:11]=1[CH:12]=[N:1][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:7][OH:8]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC(C)C[C@H](N)CO
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1F

Procedure:
A solution of (S)-(+)-leucinol (2.47 g, 21 mmol) and 2,4-difluorobenzaldehyde (3 g, 21 mmol) in benzene (50 mL) was heated to reflux for 4 hours during which time water was collected in a Dean-Stark trap. The solvent was evaporated in vacuum to give (2S)-2-[(2,4-difluorobenzylidene)-amino]-4-methylpentan-1-ol.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[F:10][C:11]([F:22])([F:21])[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH:37]=[CH:38][N:39]=1)[C:27]([NH:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([NH:29][C:27](=[O:28])[C:26]1[CH:37]=[CH:38][N:39]=[C:24]([NH:23][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=2)[CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Solvent: O=C(Cl)c1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2ccc(C(F)(F)F)cc2)c1
Yield: 60 %

Procedure:
Following the procedure as describe in preparation of Example 5, variations as required to replace benzoyl chloride with 4-(trifluoromethy)benzoyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(4-trifluoromethylbenzoylamino)-isonicotinamide was obtained in 60% yield: mp 181-183° C.; 1H NMR (300 MHz, CDCl3) δ 8.92 (br s, 1H), 8.61 (s, 1H), 8.32 (d, J=4.3 Hz, 1H), 7.97 (d, J=7.8 Hz, 2H), 7.73 (d, J=7.8 Hz, 2H), 7.53 (d, J=4.3 Hz, 1H), 7.38-7.15 (m, 5H), 6.98 (br s, 1H), 4.63 (d, J=5.7 Hz, 2H); MS (ES+) m/z 400.4 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].CC1C=CC(S(O[CH2:34][C:35]2([CH3:39])[CH2:38][O:37][CH2:36]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:34][C:35]1([CH2:39][N:10]2[C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=3[C:8]([C:11]3[CH:12]=[CH:13][C:14]([S:17]([NH2:20])(=[O:19])=[O:18])=[CH:15][CH:16]=3)=[N:9]2)[CH2:38][O:37][CH2:36]1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Reactant: NS(=O)(=O)c1ccc(-c2n[nH]c3cc[nH]c(=O)c23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(Cn2nc(-c3ccc(S(N)(=O)=O)cc3)c3c(=O)[nH]ccc32)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (34.5 mg) in DMF (2 mL) was added sodium hydride (60% dispersion in mineral oil, 7.13 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (45.7 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (14.2 mg).
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:17][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)c1ccc(C#CCCCO)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
Methyl 4-iodobenzoate (13.1 g, 60 mmol), PdCl2(PPh3)2 (2.0 g, 3 mmol), and CuI (855 mg, 4.5 mmol) were added to TEA (60 mL). The mixture is degassed while stirring by bubbling N2 vigorously into the solution. Pent-4-yn-1-ol (5.5 g, 66 mmol) was added by syringe. The mixture was heated at 90° C. overnight. After cooling, the crude mixture was concentrated by rotary evaporation and pumped on the high vacuum for 1 h. The oil was dissolved in DCM and adsorbed onto Celite followed by purification by chromatography (gradient 10-100% EtOAc/Hexanes) to give the title compound as a light yellow powder (9 g, 69%). 1H NMR (400 MHz, CDCl3) δ 7.95 (dd, 2H, J=9.0, 1.5 Hz), 7.44 (dd, 2H, J=9.0, 1.5 Hz), 3.90 (s, 3H), 3.85 (m, 2H), 2.57 (t, 2H, J=5.5 Hz), 1.87 (m, 2H), 1.42 (t, 1H, J=5.5 Hz); ES/MS calcd. for C13H16O3+ 219.1, found m/z=219 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][CH2:8][N:7]1[C:17](=O)[CH3:18].[NH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:22]=1[C:23]#[N:24].C(=O)(O)[O-].[Na+]>ClCCl.O>[Cl:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:21]([N:20]=[C:17]([N:7]2[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:6]2)[CH3:18])[C:22]=1[C:23]#[N:24]
Reactant: N#Cc1c(N)cccc1Cl
Reactant: CC(=O)N1CCCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=Nc1cccc(Cl)c1C#N)N1CCCc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.9 %

Procedure:
Phosphorus oxychloride (2.93 mL, 32.0 mmol) was added to a stirred solution of 1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)ethanone (5.5 g, 29.0 mmol) in dry dichloromethane (100 mL) at 10° C. After that, the mixture was stirred for 20 minutes at room temperature. Then a solution of 2-amino-6-chloro-benzonitrile (4.43 g, 29.0 mmol) in dry dichloromethane (40 mL) was added and the resulting suspension was heated under reflux for 24 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added followed by saturated sodium bicarbonate to pH 8. The organic layer was separated and the aqueous was extracted with dichloromethane (100 mL). The organic fraction was washed with brine and dried over sodium sulfate, and then evaporated in vacuo to give a residue which was precipitated in ether. The solid was collected by filtration and dried in vacuo to give 6 g of product as a brown powder (yield was 63.7%). It was used in the next step without further purification. MS obsd. (ESI+) [(M+H)+] 324.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:24][C:20]4([CH2:23][CH2:22][CH2:21]4)[O:19][N:18]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.[F:26][C:27]1[C:28]([C@H:34]([NH2:36])[CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:26][C:27]1[C:28]([C@H:34]([NH:36][C:11](=[O:13])[C:10]2[CH:14]=[C:15]([C:17]3[CH2:24][C:20]4([CH2:21][CH2:22][CH2:23]4)[O:19][N:18]=3)[CH:16]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:9]=2)[CH3:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: C[C@@H](N)c1ncc(F)cc1F
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C3=NOC4(CCC4)C3)c2)nc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ncc(F)cc3F)cc(C3=NOC4(CCC4)C3)c2)nc1
Yield: 57.9 %

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(5-oxa-6-azaspiro[3.4]oct-6-en-7-yl)benzoic acid (0.20 g, 0.56 mmol) in N,N-dimethylformamide (2.5 mL) were added (1R)-1-(3,5-difluoropyridin-2-yl)ethanamine hydrochloride salt (0.13 g, 0.67 mmol), EDC (0.16 g, 0.70 mmol), HOAT (0.5 M in DMF; 0.56 mL, 0.28 mmol) and diisopropylethylamine (0.09 mL, 0.56 mmol). The reaction mixture was at ambient temperature and solid was filtered off. Purification by reverse phase HPLC(C-18, 95% water/acetonitrile 5% water/acetonitrile with 0.1% trifluoroacetic acid). Clean fractions were combined and saturated aqueous NaHCO3 was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with water (3×), brine, dried over sodium sulfate, filtered and concentrated gave the title compound (150 mg). HRMS 463.1948 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H); 8.44 (t, J=1.7 Hz, 1H); 8.38 (t, J=1.6 Hz, 1H); 8.29 (d, J=2.4 Hz, 1H); 8.14 (t, J=1.6 Hz, 1H); 7.71 (d, J=8.1 Hz, 1H); 7.63 (d, J=7.6 Hz, 1H); 7.58 (dd, J=8.1, 2.2 Hz, 1H); 7.24-7.16 (m, 1H); 5.71-5.61 (m, 1H); 3.51 (s, 2H); 2.62-2.50 (m, 2H); 2.37 (s, 3H); 2.26-2.18 (m, 2H); 1.90-1.79 (m, 1H); 1.68-161 (m, 1H); 1.54 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[C:35](SC)SC)[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][NH2:42].O.[NH2:44][NH2:45]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:44][NH:45][C:35]([NH:42][CH3:41])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CSC(SC)=C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Reactant: CN
Reactant: NN
Solvent: CCO
Solvent: O
Product: CNc1[nH]nc2c1CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 80 °C
Yield: 50.1 %

Procedure:
To a solution of tert-butyl(1-(4-(6-(bis(methylthio)methylene)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (100 mg, 0.18 mmol) in ethanol (873 μl) was added methylamine (2M in THF, 87 μl, 0.18 mmol) and the mixture heated to 80° C. under a nitrogen atmosphere for 2 hours. Further methylamine (2M in THF, 873 μl, 1.746 mmol) was added and the mixture heated to 80° C. under a nitrogen atmosphere for 2 hours. Hydrazine monohydrate (25.4 μl, 0.52 mmol) was added and the mixture heated to 80° C. for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure and purified via Biotage chromatography (silica, DCM: MeOH, gradient elution from 100:0 to 90:10) to give a colourless solid (47 mg, 52% yield). 1H-NMR (500 MHz, CDCl3) δ 7.63 (1H, s), 7.32 (2H, d), 7.27 (2H, d), 7.16-7.22 (3H, m), 7.09-7.16 (2H, m), 5.06 (1H, br s), 3.10 (2H, t), 2.68 (3H, s), 2.22-2.60 (6H, br m), 1.97-2.09 (1H, m), 1.72-1.84 (1H, m), 1.03-1.53 (9H, br m). LCMS (Method A) RT=5.34 min, M+H+=522.19.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[O:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][CH:10]([C:11]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[O:12])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:8])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)NCC(=O)c2ccco2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC(NC(=O)c1ccc(OC)cc1)C(=O)c1ccco1
Yield: 73 %

Procedure:
11.0 g of N-(4-methoxybenzoyl)-(2-furylcarbonyl)methylamine, 2.0 g of 61% sodium hydride and 7.8 g of ethyl bromoacetate are treated in the same manner ad described in Preparation 1-(2). 10.7 g of ethyl 3-(4-methoxybenzoylamino)-3-(2-furylcarbonyl)propionate are thereby obtained. Yield: 72.8%
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][C:13]([Br:16])=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C([O-])([O-])=O.[K+].[K+].[SH:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>CN(C=O)C.O>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([S:26][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][C:13]([Br:16])=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])=[CH:28][CH:29]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1ccc(Br)s1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
The product of Example 241b (1.50 g, 4.34 mmol) was dissolved in DMF to which K2CO3 (1.20 g, 8.69 mmol), and 4-mercapto-phenol (548 mg, 4.34 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.54 g, 78%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=S)[NH:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[ClH:12].[CH:1]1([NH:7][C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[NH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)NC1CCCCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NC2CCCCC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 34.7 g (0.2 mole) of 4-cyclohexyl-3-thiosemicarbazide and 32.9 g (0.2 mole) of ethyl 2-chloroacetoacetate in 350 mL of absolute ethanol was stirred under nitrogen atmosphere at ambient temperature for 2 hr, treated with 100 mL of 2N ethanolic hydrogen chloride and heated at reflux for 2 hr. The hot reaction mixture was filtered to remove an amorphous solid. The product persistently crystallized in the filter. The product was recrystallized from acetone and recovered by decating off hot acetone solvent and washing the residue with cold acetone to give 27 g of large, off-white crystals, mp 178-182° C.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[O:17][CH3:18].[CH3:19]O>>[CH3:19][O:15][C:14](=[O:16])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([OH:6])=[C:8]([O:17][CH3:18])[CH:9]=1
Reactant: CO
Reactant: COc1cc(CC(=O)O)ccc1O
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(O)c(OC)c1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
Concentrated sulfuric acid (12 ml) was added to a solution of (4-hydroxy-3-methyoxy-phenyl)-acetic acid (22.5 g, 123 mmol) in methanol (450 ml) at room temperature, and the reaction was heated to 90° C. for 2.45 hours. The reaction was then cooled to room temperature and stirred for 18 hours, and the solvent was removed under reduced pressure. The residue was suspended in ice water (300 ml) and extracted with diethylether (2×300 ml). The combined organic extracts were washed with saturated sodium bicarbonate solution (2×100 ml), brine (100 ml), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (80:20 changing to 70:30, 60:40 and finally 1:1, by volume) to give (4-hydroxy-3-methoxy-phenyl)-acetic acid methyl ester (23 g) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ=6.82-6.85 (1H, d), 6.80 (1H, s), 6.76-6.79 (1H, d), 5.49 (1H 3.66 (3H, s), 3.53 (2H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 219.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.Cl.[NH:18]([C:20]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][N:21]=1)[NH2:19]>CC(O)=O>[C:26]([C:24]1[CH:23]=[CH:22][N:21]=[C:20]([N:18]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:19]2)[CH:25]=1)#[N:27]
Reactant: N#Cc1ccnc(NN)c1
Reactant: COC(=O)C(=O)CC(=O)c1ccc(C)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccc(C)cc2)n(-c2cc(C#N)ccn2)n1
Temperature: 25 °C
Yield: 8.5 %

Procedure:
A solution of methyl 4-(4-methylphenyl)-2,4-dioxobutanoate (500 mg, 22.7 mmol) and 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (500 mg, 24.2 mmol, PREPARATION 3) in AcOH (10 mL) was heated at 100° C. for 30 min and cooled to rt. The solution was concentrated to an oily residue which was partitioned between EtOAc (50 mL) and water (50 mL). The pH was adjusted to pH=8 using a saturated aq. Na2CO3 solution. The organics were dried (MgSO4), filtered, and concentrated to give a solid which was triturated with MTBE/hexanes (1:1) and filtered to give the title compound (613 mg, 85%) as a yellow solid. 1H NMR (400 MHz, CD3OD): δ 2.48 (3H, s), 3.92 (3H, s), 7.01 (1H, s), 7.08-7.21 (4H, m), 7.71 (1H, d, J=4.8 Hz), 8.12 (1H, s), 8.48 (1H, d, J=4.8 Hz), 8.00 (1H, s), 8.48 (1H, d, J=8 Hz).
Reaction SMILES: [N:1]1[CH:6]=CC=C[CH:2]=1.Cl.C([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2SC=1C(Cl)=O)CC.C(OC(CCNC1C=C(Cl)C=C(Cl)C=1)=O)C>CN(C)C=O>[CH3:11][NH:15][C:16]1[CH:2]=[N:1][CH:6]=[C:18]([NH:19][CH3:14])[CH:17]=1
Reactant: c1ccncc1
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Agent: CCOC(=O)CCNc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Product: CNc1cncc(NC)c1

Procedure:
In the mixture of 30 ml of pyridine and 3 ml of dimethylformamide was suspended 1.09 g of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension was added 1.02 g of N-(2-ethoxycarbonylethyl)-3,5-dichloro-aniline obtained in Reference Example 5 and 47.4 mg of 3,5-dimethylaminopyridine, followed by stirring at 70° C. for 20 hours. The reaction mixture was concentrated and to the mixture was added saturated sodium hydrogencarbonate aqueous solution. The organic layer was extracted with chloroform. The extact was washed with water and dried, followed by removing the solvent. The residue was dissolved in ethanol and to the solution was added saturated hydrogenchloride diethylether solution. The mixture was stirred at room temperature and the solvent was removed under reduced pressure. The residue was purified by column chromatography using a mixed solvent of chloroform and methanol (10:1 by volume) as an eluent. The resulting substance was crystallized from a mixed solvent of ethanol and diethylether. The formed crystals were recrystallized from a mixed solvent methanol and diethylether to obtain 109 mg of the titled compound.