Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.N1CCNCC1.[CH:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O.C1(C)C=CC=CC=1>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]2[O:7][CH:15]([OH:24])[CH2:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=CC=Cc1ccccc1
Agent: C1CNCCN1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)C(c1ccccc1)CC(O)O2
Temperature: 80 °C

Procedure:
To a solution of p-cresol (25 g, 0.231 mol, 1 equiv), piperazine (11.94 g, 0.139 mol, 0.6 equiv) and toluene (250 ml, 10 ml/g) at reflux under Dean & Stark conditions was added cinnamaldehyde (45.83 g, 44 ml, 0.347 mol, 1.5 equiv) over a 2 hour period and reaction mixture monitored by HPLC for the presence of p-cresol. Upon completion (2 to 3 hours), the mixture was cooled to 80° C. and a solution of c.HCl (25 ml, 0.301 mol, 1.3 equiv) in water (100 ml, 5 ml/g) was slowly added and heated at 80-90° C. for at least 5 hours. The resulting solution was allowed to cool to room temperature and the phases separated. The toluene solution was washed with 1M HCl (125 ml, 5 ml/g), then water (3×125 ml). The resulting organic layer was taken into the reductive amination step (Step B) as a crude mixture.
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)C1)CO>>[F:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[CH:42][CH:43]=1
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Reactant: N[C@H](CO)CCN1CC(Cc2ccc(F)cc2)C1
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Cc3ccc(F)cc3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-fluoro-benzyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13](=[NH:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:6]=1)#[N:2].C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C.CO>CN(C=O)C>[CH2:14]([C:13]1[N:12]([CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[C:1]#[N:2])=[CH:6][CH:7]=2)[C:26](=[O:25])[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][N:18]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCCC(=N)NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(=O)OCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound is prepared by stirring one equivalent of N-[(2'-cyanobiphen-4-yl)-methyl]valeramidine with diethyl ethoxymethylenemalonate (Aldrich) in a suitable solvent such as methanol or DMF. After the initial adduct is formed, one equivalent of base such as sodium methoxide is added then the material is stirred for an additional period of time, possibly with heating. Standard workup procedures appropriate to the chosen reaction solvent should be followed.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:33](=[O:49])[N:34]([CH2:38][CH2:39][CH2:40][OH:41])[CH2:35][CH2:36][CH3:37])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(NC(=O)OC(C)(C)C)CC(C(=O)N(CCC)CCCO[Si](C)(C)C(C)(C)C)=C3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOC(=O)Cc1ccc(-c2ccc3c(c2)N=C(N)CC(C(=O)N(CCC)CCCO)=C3)cc1
Reaction time: 1 h

Procedure:
Propyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded propyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, DMSO-d6) δ 7.60-7.68 (m, 2H), 7.20-7.41 (m, 5H), 6.73-6.85 (m, 3H), 4.42-4.52 (m, 1H), 4.05-4.16 (m, 2H), 3.71 (s, 2H), 3.24-3.52 (m, 6H, partially obscured by water peak), 2.75 (s, 2H), 1.66-1.78 (m, 2H), 1.50-1.65 (m, 2H), 1.15-1.23 (m, 3H), 0.75-0.92 (m, 3H); m/z (APCI-pos) M+1=464.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[I-:10].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.Cl>CN(C=O)C.O>[I:10][C:8]1[CH:7]=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [I-]
Reactant: COc1cccc(O)c1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(O)ccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Methoxyphenol (2.0 ml, 18.2 mmol) was dissolved in dry DMF (50 ml). Sodium iodide (3.3 g, 21.9 mmol) and chloramine-T (5.0 g, 21.9 mmol) was added to the mixture and the reaction was stirred at room temperature for one hour. The reaction mixture was diluted with water (150 ml), acidified with 5% hydrochloric acid solution and extracted with ethyl acetate (2×100 ml). The organic layer was washed with 5% sodium thiosulphate solution (200 ml) and dried over sodium sulphate. The product was purified by flash chromatography on silica gel twice (first with dichloromethane, then with 20% ethyl acetate in petroleum ether). The yield was 0.82 g (18%). 1H NMR (CDCl3, 500 MHz): δ 7.52 (1H, d, J=8.5 Hz), 6.63 (1H, d, J=3.0 Hz), 6.37 (1H, dd, J=8.5 Hz, 3.0 Hz), 5.27 (1H, s), 3.81 (3H, s).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:21])[C:7]([S:18]([CH3:20])=O)=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3].[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H](S)[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24].CC(N(C)C)=O>CN(C)C=O>[CH2:22]([O:25][C:26]([N:28]1[CH2:32][C@@H:20]([S:18][C:7]2[C@H:6]([CH3:21])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:30][C@H:29]1[CH2:34][O:35][CH2:36][CH2:37][F:38])=[O:27])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1COCCF
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCF)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
To a mixture of allyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (150 mg) and silica gel (300 mg) in N,N-dimethylformamide (1.5 ml) was added a solution of (2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)-4-mercaptopyrrolidine (150 mg) i dimethylacetamide (1.45 g). The mixture was stirred for 2 hours at ambient temperature. Silica gel was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to afford allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-fluoroethoxymethyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (160 mg).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OCC(C)(C)CO2)=[CH:20][CH:19]=1.CCO>COCCOC.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:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)COB(c2ccc(F)cc2)OC1
Reactant: O=C(O)c1cccc(Br)n1
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: O=C(O)c1cccc(-c2ccc(F)cc2)n1
Temperature: 100 °C
Yield: 46 %

Procedure:
A solution of 6-bromopicolinic acid (Aldrich) (2.02 g, 10 mmol) in DME containing 4 mL of 10% aq Na2CO3 was purged with Ar gas. To this mixture was added Pd(PPh3)4 followed by 2-(4-fluorophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (2.40 g, 11.5 mmol, Wako Pure Chemical Industries, Ltd) and EtOH (20 mL), and the mixture was purged with Ar gas. The reaction mixture was heated at 100° C. for 2.5 h in a sealed tube. Additional 2-bromopicolinic acid (900 mg) and Pd (OAc)2 was added, and after purging with Ar gas it was heated at 100° C. for 4.5 h. Trifluoroacteic acid (20 mL) was added to the reaction mixture, concentrated and MeOH (150 mL) was added to the residue. The insoluble material was filtered, and the filtrate solution was concentrated. Purification by flash column on silica gel eluting with EtOAc/MeOH//900:100 followed by EtOAc/MeOH/HOAc//700:1500:50 provided the desired product (1.0 g, 40% based on borinane starting material) as a white solid. 1H NMR (CD3OD) δ 8.01 (d, 1H, J=7.7 Hz), 7.94-7.87 (m, 3H), 7.73 (d, 1H, J=7.7 Hz), 7.13 (t, 2H, 8.8 Hz); MS(ESI+) m/z 234 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CCCCOC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCCC(Nc1ccc(C(=O)NCCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a mixture of ethyl 3-{[(4-{[5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}phenyl)carbonyl]amino}propanoate (489 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration, and the obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (453 mg, 98%) as a pale-brown solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][CH:9]2[CH2:11][CH2:10]2)[C:6](=[O:12])[NH:5][C:4](=[O:13])[CH:3]=1.[NH2:14][NH2:15]>C(O)C>[CH:9]1([CH2:8][N:7]2[C:2]([NH:14][NH2:15])=[CH:3][C:4](=[O:13])[NH:5][C:6]2=[O:12])[CH2:11][CH2:10]1
Reactant: O=c1cc(Cl)n(CC2CC2)c(=O)[nH]1
Reactant: NN
Solvent: CCO
Product: NNc1cc(=O)[nH]c(=O)n1CC1CC1
Temperature: 82.5 °C

Procedure:
6-Chloro-1-cyclopropylmethyluracil (24.34 g, 0.12 mol) was suspended in absolute ethanol (245 mL) under nitrogen. Anhydrous hydrazine (11.69 g, 0.36 mol) was added via syringe in excess, resulting in a clear-yellow solution. The reaction mixture was heated at 80-85° C. for one hour; bright yellow crystals began forming within minutes of the application of heat. The reaction mixture was cooled to room temperature and then in an ice bath, and the crude product collected by filtration. N2H4×HCl was removed by triturating with cold water to give the product as a pale yellow solid, 20.47 g (86%). Mp 221° C. (dec).
Reaction SMILES: [CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[N:30]=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:28]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=2[F:44])=[CH:27][CH:26]=1.O>CN(C=O)C>[CH2:1]([N:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=3[F:44])=[C:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:30]=2)[CH:11]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)CN(CC)c1cccc(O)c1
Reactant: COc1ccc(F)c(-c2ccc(CBr)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CC)c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 2-(ethyl(3-hydroxyphenyl)amino)acetate (122 mg) in DMF (5.0 mL) were added potassium carbonate (75 mg) and 6-(bromomethyl)-3-(2-fluoro-5-methoxyphenyl)-2-neopentylpyridine (100 mg), and the mixture was stirred at 80° C. for 1 hr. The mixture was allowed to cool to room temperature, and water was added. The reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (107 mg) as a colorless oil.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:27])[NH:9][C:10]2[S:14][N:13]=[C:12]([S:15]CC3C=CC(OC)=CC=3)[C:11]=2[C:25]#[N:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:1]1([O:7][C:8](=[O:27])[NH:9][C:10]2[S:14][N:13]=[C:12]([SH:15])[C:11]=2[C:25]#[N:26])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CSc2nsc(NC(=O)Oc3ccccc3)c2C#N)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(S)nsc1NC(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 101 %

Procedure:
To a mixture of [4-cyano-3-(4-methoxy-benzylsulfanyl)-isothiazol-5-yl)-carbamic acid phenyl ester (1.0 g, 2.5 mmol), trifluoracetic acid (26 mL) and anisole (2.7 g, 25 mmol) at 0° C. was added mercuric acetate (0.80 g, 2.5 mmol). The mixture was allowed to warm to room temperature overnight. After concentration in vacuo, the mixture was diluted with 100 mL of water and 100 mL of ethyl acetate. Hydrogen sulfide was bubbled in slowly until precipitation of the mercury salts was complete. The mixture was diluted with brine, extracted 3× with 200 mL of ethyl acetate, and the combined organic layers were filtered through celite, dried over Na2SO4, filtered and concentrated in vacuo, affording 0.70 g (100%) of (4-cyano-3-mercapto-isothiazol-5-yl)-carbamic acid phenyl ester as a colorless solid. 1H NMR (400 MHz, acetone-d6) δ 7.47 (t, 2H, J=7.6 Hz), 7.35-7.30 (m, 3H) ppm; MS (APCI, m/z): 276 [M−H]−.
Reaction SMILES: [C:1]([C:3](=[C:7](SC)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[C:18]1([CH3:26])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][NH2:25].[OH-].[Na+].C(OCC)(=O)C>CCCCCC>[NH2:2][C:1]1[N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:26])[N:25]=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: Cc1ccccc1NN
Reactant: CSC(=C(C#N)C(N)=O)c1ccc(C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(-c2nn(-c3ccccc3C)c(N)c2C(N)=O)cc1
Yield: 4.9 %

Procedure:
The title compound was prepared from 2-cyano-3-methylthio-3-(4-tolyl) acrylamide (464 mg, 2.0 mmol), 2-tolylhydrazine hydrochloride (350 mg, 2.2 mmol) and sodium hydroxide (88 mg, 2.2 mmol) following the procedure used for the compound of Example 12. The crude product was subjected to column chromatography (SiO2, 75% ethyl acetate in hexane) to give the title compound as a yellow solid (30 mg) m.p. 133-135°. δH (CDCl3) 7.52 (2H, d, J 8.1 Hz), 7.38 (4H, m), 7.28 (2H, d, J 7.4 Hz), 5.40 (4H, m), 2.40 (3H, s) and 2.23 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[N:5][N:6]=1.[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(Cl)Cl>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:22][C:23](=[O:24])[N:6]2[N:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCSc1nnc(N)s1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCSc1nn2c(=O)cc(-c3ccccc3)nc2s1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Three point seven (3.7) grams of 2-amino-5-hexylthio-1,3,4-thiadiazole, 3.4 g of ethyl benzoylacetate and 5 g of polyphosphoric acid were mixed and stirred at 130°-140° C. for 30 minutes. After cooling, chloroform and water were added to the mixture and extraction was carried out. The organic layer was washed with a sodium hydrogen carbonate aqueous solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 5.5 g of 2-hexylthio-7-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 99%. This substance was recrystallized from ethanol and the purified compound showed a m.p. of 90°-91° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1.CCOC(C)=O>[C:9]([O:8][CH2:7][C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccsc1CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCc1sccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 62.2 (0.87 g, 6.79 mmol) in pyridine (20 mL) was added acetic anhydride (0.8 mL, 8.14 mmol) at room temperature. The mixture was stirred overnight at room temperature, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), and concentrated. The crude product was chromatographed on silica gel (0-15% EtOAc/hexane) to afford 62.3. 1H NMR (400 MHz, CDCl3) δ 7.21 (d, 1H), 6.84 (d, 1H), 5.20 (s, 2H), 2.26 (s, 3H), 2.08 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=2[F:1])[C:6]#[N:7])=[CH:20][CH:19]=1
Reactant: N#Cc1ccc(F)c(O)c1
Reactant: O=C(CBr)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(F)c(OCC(=O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Yield: 102 %

Procedure:
4-Fluoro-3-hydroxy-benzonitrile (15 g), 2-bromo-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (45 g), and potassium carbonate 45 g) were suspended together in 630 mL acetone with stirring. The mixture continued to stir for 18 hours, then was concentrated to dryness. The solid residue was taken up in 500 mL diethyl ether and stirred 1.5 h, then 1 L water was added and stirred vigorously an additional 3 hours. The solid product was collected by filtration and washed with 200 mL diethyl ether three times. It was then dissolved in THF, filtered to remove any remaining inorganic salt, and evaporated again to dryness. After drying under vacuum 18 h, 48 g of desired product was obtained (quantitative). 1H NMR (400 MHz, DMSO-d6): 7.97 (d, 2H), 7.66 (d, 1H), 7.45 (m, 2H), 7.46 (m, 3H), 7.16 (d, 2H), 5.72 (s, 2H), 5.25 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](O)[CH3:9].CCN(CC)CC.CS(Cl)(=O)=O.Cl.[NH:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:24]1[C:30]2[CH:31]=[CH:32][S:33][C:29]=2[C:28](=[O:34])[NH:27][CH2:26][CH2:25]1)[CH3:9]
Reactant: CC(O)c1ccccc1Cl
Reactant: O=C1NCCNc2ccsc21
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(c1ccccc1Cl)N1CCNC(=O)c2sccc21
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 3.4 %

Procedure:
1-(2-Chloro-phenyl)-ethanol (1.0 g, 6.39 mmol, 3.6 Eq) and Et3N (1.16 mL, 8.30 mmol, 4.7 Eq) were dissolved in anhydrous DCM (20 mL) and cooled to 0° C. under nitrogen. MsCl (645 μL, 8.30 mmol, 4.7 Eq) was added portionwise. After 3.5 hours, the reaction was poured into 1M HCl (20 mL) and the layers separated. The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic extracts washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in dioxane (6 mL) and 1,2,3,4-tetrahydro-thieno[3,2-e][1,4]diazepin-5-one (300 mg, 1.78 mmol, 1.0 Eq) was added and the reaction heated at reflux overnight. The reaction was cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by column chromatography (ISCO™ Companion©, 40 g column, 0 to 10% MeOH/DCM) to give the title compound as an off-white solid (178 mg, 0.06 mmol, 33%); 1H NMR (DMSO D6) 1.50 (3H, d), 2.92-2.99 (1H, m), 3.13 (1H, m), 3.20-3.25 (2H, m), 5.32 (1H, dd), 6.91 (1H, d), 7.25-7.35 (2H, m), 7.36-7.41 (2H, m), 7.58 (1H, d), 7.61-7.63 (1H, m); LC/MS M+1 (obs.) 307.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([C:35]([F:38])([F:37])[F:36])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH:9]([CH3:25])[C:10]([C:16]1[CH:17]=[C:18]([CH3:24])[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:13])([F:14])[F:12])[O:8][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([C:35]([F:36])([F:38])[F:37])[CH:28]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a stirred solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1H-pyridin-2-one (Example 203, step 5, 80 mg) in N,N-dimethylacetamide (1.5 ml) were added 4-fluoro-2-(trifluormethyl)benzaldehyde (63 mg) and cesium carbonate (208 mg). The mixture was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>0:1) to give the title compound (111 mg) as an off-white solid. MS (m/e)=548.2 [M+H+].