Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]([CH3:5])([CH3:4])[CH3:3].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Na+].O.[Br-].[Na+]>C1COCC1>[CH:6]1([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: c1cc[cH-]c1
Reactant: CC(C)(C)Br
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C1C=CC=C1
Temperature: 25 °C

Procedure:
2-Bromo-2-methyl propane (353.5 g, 2.582 mol, Aldrich) was transferred into a 2-1 reaction flask with side-arms at 5° C. Sodium cyclopentadienide (1290 cm3 of a 2.0M solution in THF, 2.582 mol, Aldrich) was slowly added. After complete addition, the reaction set-up was allowed to warm up to ambient temperature over 12 hours. Distilled water was added to dissolve the resulting sodium bromide and the THF solution was collected over anhydrous sodium sulfate. The aqueous layer was repeatedly extracted with diethyl ether and combined with the THF solution. Filtration afforded the crude 2-cyclopentadienyl-2-methyl propane (t-BuCp), the solvent was removed and the crude product was fractionally distilled to obtain the pure (t-BuCp), boiling point 125° C. A sample of the pure t-BuCp (42.81 g, 0.351 mol) and THF (400 cm3) were transferred into a 1-1 reaction flask equipped with a mechanical stirrer. n-Butyl lithium (223 cm3 of a 1.6M solution in hexanes, 0.357 mol, Aldrich) was added dropwise at ambient temperature. The mixture was vigorously stirred for 3 hours and the resulting solution of t-BuC5H4 -Li+ was slowly added to a suspension of ZrCl4 (40.78 g, 0.175 mol) in THF (100 cm3) at -78° C. After complete addition of the lithiated salt, stirring continued and the reaction slowly warmed up to ambient temperature over 12 h. The solvent was stripped off under reduced pressure and the crude product was Soxhlet extracted in toluene to yield crystals, after cooling, of (t-BuCp)2ZrCl2. FIGS. 1 and 2 show the 'H NMR traces (400 MHz) for Bis(i-PropylCyclopentadienyl) Zirconium Dichloride and Bis(t-ButylCyclopentadienyl) Zirconium Dichloride, respectively.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][Cl:15])[C:8]([OH:10])=[O:9])[N:6]=1.[C:16](OC(=O)C)(=[O:18])C.C(O)=O>O1CCCC1>[CH:16]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][Cl:15])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:18]
Reactant: Nc1nc(C(=NOCCCl)C(=O)O)cs1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1nc(C(=NOCCCl)C(=O)O)cs1
Yield: 80.3 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 15 g.), acetic anhydride (24.5 g.), formic acid (11.0 g.) and tetrahydrofuran (50 ml.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 13.4 g.), mp 155° C. (dec.).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH:6]1[CH:11]=[C:10]([CH:12]([OH:21])[C:13]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[N:9]=[CH:8][CH:7]=1>C(#N)C>[Cl:1][CH2:2][C:3]([O:14][CH:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[C:12]([C:10]1[CH:11]=[CH:6][CH:7]=[CH:8][N:9]=1)=[O:21])=[O:4]
Reactant: O=C(c1ccccn1)C(O)c1ccccn1
Reactant: O=C(Cl)CCl
Solvent: CC#N
Product: O=C(CCl)OC(C(=O)c1ccccn1)c1ccccn1
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (1.4 g, 0.0123 mole) in an equal amount of dry acetonitrile was added dropwise with stirring to 5.4 g (0.0252 mole) of α-pyridoin in 50 ml of dry acetonitrile. The reaction mixture was stirred one hour. The orange solid was filtered off and washed with acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[NH:12][C:13](=[O:23])[C:14]([NH:16][CH2:17][CH:18](OC)OC)=[O:15].FC(F)(F)C(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:18]=[CH:17][NH:16][C:14](=[O:15])[C:13]1=[O:23]
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)C(=O)NCC(OC)OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COC(=O)c1ccc(Cl)c(-n2cc[nH]c(=O)c2=O)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 115.6 %

Procedure:
A suspension of methyl 4-chloro-3-{[[(2,2-dimethoxyethyl)amino](oxo)acetyl]amino}benzoate (Example 330c, 8.5 g) in acetic acid (26 mL) was treated with trifluoroacetic acid (8.5 mL) under nitrogen. The resulting mixture was stirred at 120° C. for 3 h. The mixture was quenched with water (20 mL) and the resulting solid filtered off to give the subtitle compound (8.00 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:31]([CH3:33])[CH3:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:31]([CH3:32])[CH3:33])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[O:16])[CH2:18][CH2:19]1)=[O:25])([CH3:28])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2n1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.8 %

Procedure:
To a solution of 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid ethyl ester (1.60 g, 3.5 mmol) in tetrahydrofuran (10 ml), methanol (10 ml) and water (2 ml) was added lithium hydroxide monohydrate (2 eq., 168 mg). The mixture was stirred two days at room temperature. The solvent was removed under vacuum and the residue was quenched with 1M aq. dihydrogen potassium phosphate solution to pH 5. The aqueous phase was extracted with ethyl acetate (2×) and the combined organic phases washed with brine, dried over MgSO4 and filtered. The crude product was purified by column chromatography on silica gel (3:1 heptane/ethyl acetate eluant) to afford the product as an off-white powder (644 mg, 42%). MS (m/z): 430.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3](OCC)=[O:4].[O-:31][C:32]#[N:33].[K+]>C(O)CCC>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:20][C:19]=1[CH2:18][CH2:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH:2]2[O:1][C:32](=[O:31])[NH:33][C:3]2=[O:4])=[CH:11][CH:12]=1
Reactant: N#C[O-]
Reactant: CCOC(=O)C(O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [K+]
Solvent: CCCCO
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC2OC(=O)NC2=O)cc1
Yield: 62.7 %

Procedure:
A mixture of ethyl 2-hydroxy-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butyrate (0.45 g), powdery potassium cyanate (0.24 g) and butanol (20 ml) was heated for 4 days under reflux. The solvent was distilled off under reduced pressure, and the residue was acidified with 2N HCl, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform-methanol (100:3) was obtained 5-(2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]ethyl]-2,4-oxazolidinedione (0.28 g, 63%). The product was recrystallized from dichloromethane-ethanol to give colorless prisms, m.p.193-194° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:12][CH:13]([CH2:33][CH2:34][O:35]CC1C=CC=CC=1)[CH2:14][N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:22]([O:21][C:19]([NH:18][CH2:17][CH2:16][N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14][CH:13]([CH2:33][CH2:34][OH:35])[CH2:12][N:11]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCCN(CC(CCOCc1ccccc1)CN(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCN(CC(CCO)CN(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 48 h

Procedure:
N,N′-Bis(2-tert-butoxycarbonylamino-ethyl)-2-(2-benzyloxy-ethyl)-1,3-di(tert-butoxycarbonylamino)propane (3.16 g) was dissolved in absolute ethanol (100 mL) and Pd on activated carbon (1.00 g, dry, 10%) was added. The mixture was hydrogenated in a Parr hydrogenation apparatus at 35 psi for two days. The catalyst was filtered off, washed with ethanol (3×20 mL). The ethanol was removed by rotary evaporation to give a colourless oil that was dried to a constant mass (2.67 g, 97.1%) under high vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[NH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NN1CCOCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NN3CCOCC3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture is microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:9][C:10]([F:16])([F:15])[C:11](OC)=[O:12])[C:5]([N+:22]([O-])=O)=[CH:4][N:3]=1.Cl>CC(O)=O.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:22][C:11](=[O:12])[C:10]([F:16])([F:15])[CH2:9][N:8]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:6]=2[N:7]=1
Reactant: COC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Agent: Cl
Solvent: CC(=O)O
Product: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate, was dissolved in AcOH (10 mL). Iron powder (224 mg, 4 mmol) was added followed by the slow addition of HCl (1.5 mL, conc.). The reaction mixture was left to stir at 60° C. for 1 hr. The reaction was then cooled, the stir bar and unreacted iron removed by filtration through paper, and the solvent volume reduced by about 75% on a rotovap. The mixture was then diluted with ice water and EtOAc. Aqueous layer basified by careful addition of sat. NaHCO3. The organic extracts combined, dried over MgSO4, filtered and concentrated to yield 2-chloro-9-cyclopentyl-7,7-difluoro-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one as a brown syrup (550 mg) which was used directly for next step without further purification. [M+H] calc'd for C12H13ClF2N4O, 303; found 303.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([O-])(O)=O.[Na+].[CH2:43]([O:50][C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:54]3[CH:55]=[CH:56][C:51]([O:50][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[CH:52][CH:53]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(OCc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 87.2 %

Procedure:
To a solution of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.097 mmol) in DMF (1 mL) was added saturated NaHCO3, 4-benzyloxyphenylboronic acid (45 mg, 0.20 mmol) and PdCl2(Me2NPhP(tBu)2)2 (7 mg, 0.0097 mmol). The reaction was degassed for 2 minutes and then heated at 160° C., 1 h (microwave reactor). The reaction mixture was cooled to room temperature, then was diluted with EtOAc (15 mL) and washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (SiO2, 10% to 50% EtOAc in hexane) gave the title compound as a yellow solid (56 mg). 1HNMR (CDCl3) 400 MHz δ: 8.17-8.15 (m, 1H), 8.00-7.99 (m, 1H), 7.51 (d, J=8.6 Hz, 2H), 7.48-7.23 (m, 8H), 7.15-7.13 (m, 3H), 6.94 (d, J=7.4 Hz, 1H), 6.89 (d, J=8.6 Hz, 2H), 6.79 (d, J=7.4 Hz, 1H), 6.59 (dd, J=7.7, 4.9 Hz, 1H), 6.30 (s, 1H), 5.12 (br s, 1H), 5.05 (s, 2H), 2.53-2.51 (m, 4H), 2.15-2.12 (m, 1H), 1.93-1.84 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][CH:5]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:7]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>C1(C)C=CC=CC=1>[C:11]([C:3]1[C:2]([N:1]=[CH:15][N:16]([CH3:18])[CH3:17])=[N:7][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:5][N:4]=1)#[N:12]
Reactant: COC(OC)N(C)C
Reactant: CC(C)c1cnc(C#N)c(N)n1
Solvent: Cc1ccccc1
Product: CC(C)c1cnc(C#N)c(N=CN(C)C)n1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A mixture of the product from Example 244B (0.37 g, 2.28 mmol) and dimethylformamide dimethylacetal (0.30 g, 2.5 mmol, 1.1 eq) in toluene (25 mL) was heated under reflux for 1.75 h. The reaction mixture was then cooled to room temperature and the solvent evaporated under reduced pressure to provide the title compound (0.50 g, 100%) as a thick red/brown oil that was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[N+:13]([CH3:16])([O-:15])=[O:14]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([OH:12])[CH2:16][N+:13]([O-:15])=[O:14]
Reactant: C[N+](=O)[O-]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: O
Product: O=C1Nc2ccc(Cl)cc2C1(O)C[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 24 h

Procedure:
5-chloroisatin (0.09 g) and nitromethane (0.1 ml) were added to water and the reaction mixture was vigorously stirred at a temperature of 30° C. for 24 hours. The obtained product was extracted with ethyl acetate and purified by silica gel column chromatography using ethyl acetate/hexane as eluents to afford pure product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:21])[CH:12]=[C:13]([F:20])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:20][C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:21])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:22][C:23]3([C:26]([OH:28])=[O:27])[CH2:25][CH2:24]3)[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18]
Reactant: NC1(C(=O)O)CC1
Reactant: Cc1cc(F)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(F)cc2c1NC(c1cccc(NC3(C(=O)O)CC3)c1)CC2(C)C
Temperature: 25 °C
Yield: 28.4 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline (348.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 1-amino-cyclopropanecarboxylic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 1-[3-(6-fluoro-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-cyclopropanecarboxylic acid (104.8 mg, 30.1%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 369.2.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[S:21][CH:22]=[N:23][N:24]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[N:24]([CH:2]=2)[N:23]=[CH:22][S:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reactant: Nc1nncs1
Solvent: CCO
Product: COc1cc(-c2cn3ncsc3n2)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (150 mg, 0.49 mmol) and 2-amino-1,3,4-thiadiazole (49 mg, 0.49 mmol) in ethanol (3 mL) was heated to reflux for 2 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (2:1) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)imidazo[2,1-b][1,3,4]thiadiazole. 1H NMR (CD3OD, 300 MHz) δ 9.28 (s, 1H), 8.91 (s, 1H), 8.84 (d, 1H), 8.68 (dt, 1H), 8.37 (d, 1H), 8.05 (ddd, 1H), 7.85 (d, 1H), 7.81 (br s, 1H), 7.72 (dd, 1H), 4.09 (s, 3H) ppm. MS (ESI) 309 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:38])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH:27]C(OC(C)(C)C)=O)=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23>Cl.O1CCOCC1.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C@@H:14]([CH2:17][C:18](=[O:38])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=3[C:35]([OH:37])=[O:36])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCc1ccc(NC(=O)C[C@@H]2CCc3cc(Cl)cc4[nH]c(=O)c(=O)n2c34)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 184.4 %

Procedure:
A suspension of (S)-9-chloro-5-(p-tert-butoxycarbonylaminomethyl-o-carboxyphenylcarbamoylmethyl)-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]-quinoxaline-2,3-dione (430 mg) in 2N hydrogen chloride in 1,4-dioxane (14 mL) was stirred overnight at room temperature and diluted with diethyl ether. The precipitates were collected by filtration and recrystallized from water to give 350 mg of the title compound.
Reaction SMILES: [C:1]([CH:3]1[C:6]2=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2].[H-].[Na+].[CH3:15]I.O>C1COCC1.C(OCC)C>[C:1]([C:3]1([CH3:15])[C:6]2=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]2[CH2:4]1)#[N:2]
Reactant: COc1ccc2c(c1)C(C#N)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)C(C)(C#N)C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-cyano-5-methoxybenzocyclobutene (47.3 ml) in THF (300 ml) is added dropwise to a stirred suspension of NaH (23.8 g, 60% in mineral oil) and methyl iodide (37 ml) in THF (300 ml) under nitrogen and the reaction mixture is stirred at RT for three hours. H2O is added to the reaction mixture which is diluted with diethyl ether, washed with water, 10% aq. sodium sulphite, sat'd sodium chloride, dried, filtered and the filtrate evaporated in vacuo affording the desired product as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11](=[N:13][OH:14])[NH2:12])=[C:6]2[N:5]=[C:4]([C:15]([F:18])([F:17])[F:16])[CH:3]=1.[Cl:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25](Cl)=O>>[Cl:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]1[O:14][N:13]=[C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][C:4]([C:15]([F:18])([F:16])[F:17])=[N:5][C:6]=23)[N:12]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: Cc1cc(C(F)(F)F)nc2c(C(N)=NO)cnn12
Product: Cc1cc(C(F)(F)F)nc2c(-c3noc(-c4sccc4Cl)n3)cnn12

Procedure:
The title compound was prepared from 7-methyl-5-trifluoromethyl-pyrazolo[1,5-α]pyrimidine-3-amidoxime (13.8 mg, 0.0532 mmol) and 3-chloro-thiophene-2-carbonyl chloride (9.8 mg, 0.0541 mmol) similar to Example 16, and yielded 9.8 mg (48%) of an off-white solid. 1H NMR (CDCl3): 8.89 (s, 1H), 7.62 (d, J=5.22 Hz, 1H), 7.20 (d, J=0.83 Hz, 1H), 7.14 (d, J=5.22 Hz, 1H), 2.98 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[N:11]([O-])=O.[Na+].Cl[Sn]Cl>Cl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:7][NH2:11])[CH:8]=1
Reactant: O=N[O-]
Reactant: COc1ccc(Cl)cc1N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cl)cc1NN
Yield: 115.4 %

Procedure:
To a stirred suspension of 5-chloro-2-methoxyaniline (20.0 g, 126.98 mmol, 1.0 eq) in conc. HCl (250 mL) was added a solution NaNO2 (10.5 g, 152.38 mmol, 1.2 eq) in water (40 mL) dropwise at −5-0° C. until reaction mixture formed a clear solution. The reaction mixture was added dropwise to a stirred solution of SnCl2 (52.90 g, 279.36 mmol, 2.2 eq) in conc. HCl (250 mL) at −5° C. for 30 min. The solid precipitate obtained was filtered out and washed with excess of ice cold water to get (5-chloro-2-methoxyphenyl)hydrazine (25.3 g, 92%, off-white solid; TLC system: EtOAc/PE (3:7) Rf: 0.6).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[NH2:12][C:13]1[C:14](Br)=[N:15][CH:16]=[CH:17][CH:18]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:14]1[C:13]([NH2:12])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Nc1cccnc1Br
Reactant: CSc1ccccc1B(O)O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccccc1-c1ncccc1N
Temperature: 25 °C
Yield: 78.4 %

Procedure:
The 500 mL round-bottom flask, equipped with magnetic stirrer and reflux condenser was charged with 2-(methylthio)phenylboronic acid (9.48 g, 56 mmol), 3-amino-2-bromopyridine (7.15 g, 57 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos, 0.92 g, 4 mol %), Pd2(dba)3 (1.02 g, 2 mol %), potassium phosphate hydrate (39 g, 3 equivalents), 100 mL of toluene. The flask was filled with nitrogen and heated to reflux under nitrogen atmosphere for 24 hours. Then the reaction was cooled down to room temperature, diluted with 500 ml of water and extracted with ethyl acetate (5×40 mL). Organic fractions were combined, dried over sodium sulfate, filtered and evaporated. The residue was subjected to column chromatography on silica gel with eluent hexane/ethyl acetate gradient mixture, providing 2-(2-(methylthio)phenyl)pyridin-3-amine as yellow crystals (9.5 g). NMR confirmed the structure.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.Br[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>>[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])[CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: CC(Br)C(N)=O
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C(N)=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 85 %

Procedure:
The title compound was prepared in analogy to Example 10 from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and (RS)-2-bromo-propionamide with potassium carbonate as the base. Yield: 85% of theory as a white solid; MS: m/e=343 (M+H)+.